Systemic formulations of pyridinone derivatives for TG-2 related diseases

Abstract

To provide a systemic formulation for the prevention and / or treatment of TG-2-related diseases. [Solution] A systemic formulation is provided comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one polymer precipitation inhibitor.

Description

Detailed description of the invention

[0001] The present invention relates to systemic formulations, particularly oral formulations, for the prevention and / or treatment of TG-2 related diseases, such as fibrosis, particularly fibrous liver diseases including nephropathy, non-alcoholic steatohepatitis (NAFLD) and / or non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), and cystic fibrosis, and to the use thereof in the prevention and / or treatment of fibrosis, particularly fibrous liver diseases including nephropathy, NAFLD and NASH, idiopathic pulmonary fibrosis, and cystic fibrosis.

[0002] Furthermore, this application also relates to the use of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate as a hepatoprotective agent.

[0003] Furthermore, the present invention relates to a pharmaceutical composition comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate for use as a hepatoprotective agent, as demonstrated by its ability to lower serum levels of liver enzymes, and for use in protecting the liver from hepatotoxicity, improving liver function, and / or repairing liver damage, or in the prevention or treatment of liver disease or liver injury.

[0004] [Background of the Invention] Steatohepatitis is a type of fatty liver disease characterized by inflammation of the liver accompanied by simultaneous fat accumulation in hepatocytes. Simple fat deposition in the liver is called steatosis, and these combined constitute fatty liver changes.

[0005] There are two main types of fatty liver disease: alcohol-related fatty liver disease (NAFLD) 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 in either type can lead to fibrosis and subsequent progression to cirrhosis, and NASH is now considered a frequent cause of cirrhosis of unknown origin.

[0006] Diabetic nephropathy is a kidney disease that develops as a result of diabetes mellitus (DM). Diabetic nephropathy and type 2 diabetes mellitus (T2DM) are the most common causes of end-stage renal disease (ESRD). Diabetic nephropathy results in a chronic and progressive decline in kidney function to the point where patients must undergo dialysis or transplantation to survive. Microalbuminuria occurs following the initial stages of subtle morphological changes in the renal glomeruli. This is associated with a gradual increase in blood pressure and an increased incidence of cardiovascular disease. A sustained increase in urinary protein excretion occurs, and the glomerular filtration rate is determined. Diabetic nephropathy has many potential underlying pathophysiological causes, including metabolism, protein glycosylation, hemodynamics, changes in glomerular flow / pressure, development of hypertension, and cytokine production, all of which are associated with the development of extracellular matrix and increased vascular permeability, leading to glomerular damage and proteinuria.

[0007] Huang et al.(Kidney International2009,7 6,383-394) describes a dipeptide derivative (NTU281) as an irreversible TG-2 inhibitor. One drawback of the dipeptide derivative is that it must be applied topically to the kidney by an implanted osmotic pump. Given that TG2 is ubiquitous in almost all cell types and cell compartments, present on the cell surface, secreted into the extracellular matrix, and found in various organs, a systemic formulation of the dipeptide derivative by Johnson based on this teaching is not conceivable, and therefore, the application of a TG2 inhibitor is most likely to result in undesirable off-target effects.

[0008] Huang et al. describe an implanted osmotic pump containing the topical formulation NTU281 (drug) in phosphate-buffered saline as the vehicle (50 mmol / l). Therefore, the osmotic pump must be implanted through anesthesia and a related surgical intervention. While anesthesia is commonly used in the medical field, it is always associated with a significant risk of complications, especially when treating vulnerable populations such as children and the elderly. Implanting an osmotic pump into a patient's body poses additional risks to the patient, as electronic devices like pumps are sensitive under physiological conditions and can, for example, rupture, and are therefore not always reliable. Furthermore, the pump must be maintained, which causes further discomfort to the patient. Moreover, patient compliance can be significantly improved by removing the obstacles of surgical intervention. Implanted osmotic pumps containing topical formulations cannot be used in humans.

[0009] Lauzier et al. (Arthritis Research Therapy 2012,14,R159) describe the effects of cystamine or its RNA derivatives on the inhibition of TG2 by cystamine, a competitive inhibitor of TGases for infiltrative tract formation and cartilage destruction in arthritis. Cystamine is a disulfide with two amino moieties.

[0010] Luciani et al. (Nature Cell Biology 2010, 12, 863-875) describe the effects of cystamine and siRNA on lung inflammation in cystic fibrosis.

[0011] 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 halo-dihydroisoxazole-derivative transglutaminase inhibitor (KCC009) on inflammation in cystic fibrosis.

[0012] Olsen et al. (American Journal of Respiratory Cell and Molecular Biology 2014, 50, 737-747) disclose the effects of two different small electrophilic compounds, 2-cyano-3,12-dioxoliane-1,9-diene-28-oic acid, and 15-deoxy-delta-12,14-prostaglandin J2 on pulmonary fibrosis.

[0013] Sanchez-Lara et al. (Veterinary Pathology 2015, Vol.52(3)513-523) describe the effects of 1,3-dimethyl-2[(oxopropyl)thio]-imidazolium chloride (D003, Zedira), non-selective TG inhibitor NTU281, or monoclonal antibody BB7 on chronic kidney disease.

[0014] Especially in the case of systemic therapy, establishing the appropriate bioavailability of drugs under physiological conditions is still a major problem in the pharmaceutical field. An object of the present invention is to provide a method for treating diabetic nephropathy and / or non-alcoholic steatohepatitis that exhibits high anti-fibrotic effects with bioavailability and low side effects.

[0015] Another object of the present invention is to provide a compound for use as a hepatoprotecant, i.e., a hepatoprotective agent, and its use in protecting the liver against hepatotoxicity, improving liver function, protecting / repairing liver injury, and / or preventing or treating liver diseases.

[0016] The object of the present invention is solved by the teachings of the independent claims. Further advantageous features, aspects, and details of the present invention are apparent from the dependent claims, the specification, the drawings, and the examples of this application.

[0017] [Brief Description of the Invention] An object of the present invention is (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate of formula (I)

[0018] [Chemical Formula] , or a pharmaceutical formulation, preferably a systemic formulation, comprising an enantiomer, solvate, hydrate or pharmaceutically acceptable salt of formula (I). Here, the compound of formula (I) is also referred to as compound 1 or Comp1.

[0019] Unexpectedly, we were able to demonstrate that compounds according to formula (I) can be used to reduce fibrosis, particularly fibrosis caused by diabetic nephropathy and non-alcoholic steatohepatitis. This compound contains a pyridinone moiety as its main structural element. Furthermore, it is remarkable that compounds according to formula (I) can be used as a systemic formulation in the prevention and treatment of nephropathy, particularly diabetic nephropathy, hepatic fibrosis, and cystic fibrosis, i.e., the drug is distributed throughout the body via the blood or lymphatic system. This is particularly remarkable given that TG2 is ubiquitously expressed in almost all cell types and cell compartments, is present on the cell surface, secreted into the extracellular matrix, and is present in various organs, and therefore, it can be assumed that the possibility of off-target effects is highest. NASH- and mouse model studies confirm the anti-fibrotic effects on the liver and kidney achieved by administration of a systemic formulation containing compounds according to formula (I) (Examples 2 and 3). Furthermore, positive data from bioavailability studies in mice (Example 4) also confirm the bioavailability of compound (I) via systemic administration in vivo. Surprisingly, compound (I) We demonstrated that bioavailability can be significantly increased in humans through the application of systemic formulations (Example 7).

[0020] Furthermore, systemic formulations avoid means such as osmotic pumps used by Johnson et al., for example, and completely avoid the implantation of such devices. Therefore, drug administration is objectively facilitated, more reliable, and safer, and patient suffering can be significantly and objectively reduced. Formulations according to the present invention can be administered far more easily than state-of-the-art formulations. Moreover, formulations according to the present invention exhibit a higher antifibrotic effect and therefore show better outcomes in treatment.

[0021] Diabetes mellitus is also frequently associated with NASH (non-alcoholic steatohepatitis), a common cause of cirrhosis of unknown origin. It is clear that treatment for NASH and diabetic nephropathy is often required simultaneously. The systemic formulations according to the present invention can be used to simultaneously target the liver (NASH) and the kidneys (diabetic nephropathy). Similarly, cholestatic liver diseases, such as PSC (primary sclerosing cholangitis) and PBC (primary biliary cholangitis), are fibrous liver diseases often associated with cholangiopathic nephropathy caused by high exposure to endogenous bile acids, and chronic and fibrous inflammation in the kidneys. Furthermore, simultaneous treatment of the kidneys and prophylactic treatment of the liver, and vice versa, is also possible. Therefore, it is clear that the systemic formulations according to the present invention enable use in new clinical situations. Additionally, cystic fibrosis is often associated with diabetes mellitus. A systemic formulation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate was shown to exhibit the same antifibrotic effect in the liver and kidneys (Example 5).

[0022] [Description of the invention] The term “systemic formulation” refers to a pharmaceutical composition suitable for administration so that a drug or activator is delivered systemically to the entire body of an organism, such as a type of circulatory system drug, and thus affects the whole body. Administration can be done via intestinal administration (absorption of the drug through the gastrointestinal tract) or parenteral administration (e.g., lung, nasal, injection, or infusion). Preferably, the term “systemic formulation” excludes formulations for intravenous administration. The circulatory system, also called the cardiovascular system or vascular system, is the organ system that allows blood to circulate and transport nutrients (e.g., amino acids and electrolytes), oxygen, carbon dioxide, hormones, and blood cells to and from cells in the body in order to provide nourishment, and that enables the fight against disease, stabilize temperature and pH, and maintain homeostasis.

[0023] The circulatory system includes the lymphatic system, which circulates lymphatic fluid. For example, the passage of lymphatic fluid takes much longer than the passage of blood. Therefore, the term “systemic preparation” refers to a preparation in which the drug is distributed throughout the body of the organism, for example, by the vascular system or the lymphatic system throughout the body, for example, after intravenous or intramuscular injection, or after ingestion of a tablet, i.e., after intestinal administration, especially after oral or parenteral administration.

[0024] The systemic formulations disclosed herein are preferably in the form of tablets, coated tablets, capsules, powders, or granules. In contrast, a "topical preparation" is a preparation applied to a specific location on or within the body where the topical preparation is to act. "Topical" means "location," "locally," "at a specific site," "externally," or "limited to a specific part of the body." Therefore, it can reduce the risk of undesirable side effects that may occur in other parts of the organism. In most cases, topical administration involves a wide variety of preparations, including creams, foams, gels, lotions, and ointments, applied to the body surface, such as the skin or mucous membranes, to treat a disease. This means that many topical medications are transdermal, meaning they are applied directly to the skin. Topical medications may also be applied to the surface of tissues other than the skin, such as inhaled medications like asthma medications, or eye drops applied to the conjunctiva, or ear drops placed in the ear, or medications applied to the surface of teeth, or medications applied using a pump such as an osmotic pump.

[0025] Topical formulations include those for the ear, cheek, bronchus, percutaneous, inhalation, intra-articular, gluteus maximus, heart, dermal, lumbar, lymphatic, breast, nasal cavity, nerve, eye, orbit, bone, pericardium, lung, spinal cavity, trachea, urethra, uterus, ventricle, bladder, vitreous, conjunctiva, skin, nose, perineural, posterior eyeball, subconjunctival, vagina, and cilia.

[0026] As used herein, the term “parenteral formulation” refers to a formulation typically administered by injection or infusion, and includes, but is not limited to, epidural, intra-arterial, intra-venous, intratubular, intravascular, intramuscular, intraperitoneal, intrapleural, subcutaneous, subepidermal, and transdermal injections and infusions. Preferably, parenteral formulations are selected from the group including or comprising epidural, intratubular, intravascular, intramuscular, intraperitoneal, intrapleural, subcutaneous, subepidermal, and transdermal injections and infusions. Preferably, intra-arterial and intravenous formulations are excluded from parenteral formulations.

[0027] As used herein, “enteral preparations” refers to preparations of drugs that are typically absorbed through the mouth (per os, orally, perorally): such as tablets, sugar-coated tablets, capsules, juices, drops, etc. These drugs are absorbed into the bloodstream of the gastrointestinal tract, then enter the liver via the portal system, and then enter the bloodstream via the hepatic veins. As used herein, the term refers to preparations that are typically administered, including but not limited to enteral, intra-gastrointestinal, sublingual, peroral, and rectal administration. Preferably, enteral preparations consist of preparations selected from the group including or comprising enteral, intra-gastrointestinal, sublingual, peroral, and rectal administration.

[0028] As used herein, “oral preparation” refers to a preparation of a drug that is absorbed through the mouth (e.g., per os, orally, perorally, sugar-coated tablets, capsules, juices, drops, etc.). These drugs are absorbed into the bloodstream of the gastrointestinal tract, then enter the liver via the portal system, and then enter the bloodstream via the hepatic veins. As used herein, the term refers to preparations administered orally.

[0029] Systemic formulations 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 lyophilized products, lozenges, pastilles, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules, and capsules. In particular, systemic formulations can be liquid formulations including oral solutions, suspensions, emulsions, powders and granules for oral solutions and suspensions, oral drops, powders for oral drops, syrups, and powders and granules for syrups, or solid forms including uncoated tablets, coated tablets, effervescent tablets, soluble tablets, chewable tablets, oral lyophilized products, lozenges, pastilles, compressed lozenges, sublingual tablets, buccal tablets, granules, effervescent granules and capsules. Uncoated tablets and coated tablets, and capsules, are preferred pharmaceutical formulations whether hard or soft. Most preferably, the formulation is a tablet or a capsule. Examples may include water or a water / propylene glycol solution for parenteral injection, or the addition of sweeteners and opalers for oral solutions, oral suspensions, and oral emulsions. Preferably, systemic formulations are solid formulations, more preferably solid enteral formulations, and most preferably solid oral formulations.

[0030] As used herein, "topical administration" refers to the administration of a topical preparation. As used herein, "systemic administration" refers to the administration of a systemic preparation. As used herein, “topical availability” refers to the release of the drug from the formulation to a site where it is to be absorbed by a specific tissue or organ, such as from the vehicle or tablet of the formulation, and therefore the drug can act in all locations.

[0031] As used herein, "systemic availability" refers to the proportion of a drug dose that reaches the systemic circulation intact after administration via routes other than intravenous. The term "systemic availability" also refers to the extent to which a drug or other substance is taken up by specific tissues or organs after administration. For example, a drug administered orally and that overcomes the intestinal epithelial barrier is systemically available, or in other words, systemically available, because it is present in the intestinal tissue. "Systemic availability" and "systemically available" are synonymous with "bioavailability" or "bioavailable." Therefore, a compound administered topically may also exhibit systemic availability.

[0032] The term "drug level" refers to the level of a drug in plasma, tissue, or organ, while the phrase "systemic availability at target site" refers to the same aspect. As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a particular component that has the same activity as the unmodified compound and is not biologically or otherwise undesirable.

[0033] pharmaceutically acceptable salts can be formed, for example, with organic or inorganic acids. Suitable acids include acetic acid, acetylsalicylic acid, organic dicarboxylic acids, 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 acids, such as citric acid or sodium bicarbonate, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bisulfate, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconate, dodecyl sulfate, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerophosphate, and glycerolsulfonic acid. It contains syn, glucoheptanoic acid, gluconic acid, glutamic acid, glutaric acid, glycolic acid, hemisulfate, 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, mucoic acid, naphthylenesulfonic acid, naphthic acid, nicotinic acid, nitrite, oxalic acid, pelargonic acid, phosphoric acid, propionic acid, saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfate, tosylic acid, undecylenic acid, and amino acids of natural and synthetic origin. Preferably, the acid is adipic acid.

[0034] Therefore, preferred embodiments of the present invention are Equation (I):

[0035] [ka] The target is the salts of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate and adipic acid.

[0036] Other preferred embodiments of the present invention are: Equation (I):

[0037] [ka] The present invention relates to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate and a salt of adipic acid, or an enantiomer, solvate, or hydrate of formula (I) and a salt of adipic acid.

[0038] As used herein, the term “solvate” refers to compounds that form complexes through coordination with solvent molecules, particularly these forms of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

[0039] As used herein, the term “hydrate” refers to compounds that form complexes through coordination with water molecules, in particular these forms of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

[0040] In this specification, the terms “effective dose” or “therapeutic dose” in reference to an activator, or pharmaceutically active agent or drug, or active pharmaceutical ingredient are synonymous and refer to a sufficient amount of the activator, or pharmaceutically active agent or drug, or active pharmaceutical ingredient to produce the desired effect. Therefore, these amounts are low enough to treat the disease but avoid serious side effects. A therapeutic dose of a pharmaceutically active agent, when applied repeatedly over time, will result in substantial relief of the condition. The effective dose of a pharmaceutically active agent varies depending on the specific condition being treated, the severity of the condition, the duration of treatment, the specific components of the composition used, and similar factors.

[0041] As used herein, the terms “activator,” “pharmaceutically active agent,” “drug,” or “active pharmaceutical ingredient” are used synonymously herein and refer to compounds that exhibit therapeutic effects on mammals, particularly humans.

[0042] As used herein, the term "pharmaceutical composition" refers to a composition that, when administered, exhibits a therapeutic effect on mammals. The systemic formulations according to the present invention as described herein preferably comprise (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

[0043] Therefore, embodiments of the present invention are Equation (I):

[0044] [ka] The target is systemic formulations containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

[0045] Furthermore, the systemic formulation may be an enteral formulation or a parenteral formulation. Embodiments of the present invention thus relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein the systemic formulation is in the form of an enteral formulation or a parenteral formulation.

[0046] Systemic formulations are preferably in the form of oral formulations, specifically oral solid formulations. This is a specific form in enteral preparations. Therefore, preferred embodiments of the present invention relate to systemic preparations comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, where the systemic preparation is in the form of an oral preparation.

[0047] Furthermore, (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate can be administered in the form of its pharmaceutically active salt, solvate, or hydrate, optionally with essentially non-toxic and pharmaceutically acceptable excipients. The formulations are prepared in known methods on conventional solid or fluid carriers using appropriate doses of conventional pharmaceutically acceptable excipients.

[0048] Therefore, the systemic formulation according to the present invention may further contain excipients. Accordingly, embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient.

[0049] After administration of a systemic formulation, the administered drug volume must be rapidly and completely dissolved. pH fluctuations in the stomach after oral administration must be controlled to ensure that the administered drug volume is dissolved. A higher systemic availability (AUC), combined with mucosal release in the small intestine, is expected to lead to a greater pharmacological effect.

[0050] Excipients can be acidifying agents. The term "acidifying agent" refers to a substance that, when dissolved in water, produces a pH level of less than 7.0. Therefore, the systemic formulation according to the present invention may contain an acidifying agent. Acidifying agents include organic acids, such as 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 (hexanediic acid), or glutamic acid; and organic tricarboxylic acids, such as citric acid or sodium hydrogen citrate. Preferably, the acidifying agent is adipic acid.

[0051] With respect to systemic formulations disclosed herein, preferred "acidifying agents" 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, etc., and organic tricarboxylic acids such as citric acid and sodium hydrogen citrate.

[0052] A more preferred "acidifying agent" with respect to the systemic formulations disclosed herein is selected from the group consisting of adipic acid, fumaric acid, and glutaric acid. Therefore, the systemic formulation according to the present invention may contain an acidifying agent.

[0053] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or drug The present invention relates to a systemic formulation comprising or consisting of a scientifically acceptable salt and at least one excipient, wherein the at least one excipient is an acidifying agent.

[0054] Another preferred embodiment of the present invention is: The present invention relates to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or an enantiomer thereof, solvate, hydrate, or pharmaceutically acceptable salt thereof, and at least one acidifying agent.

[0055] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein the at least one excipient is an acidifying agent, wherein the at least one acidifying agent is selected from the group comprising or comprising organic dicarboxylic acids and organic tricarboxylic acids. Preferably, the at least one acidifying agent is selected from the group comprising or comprising organic dicarboxylic acids and organic tricarboxylic acids. More preferably, at least one acidifying agent is selected from the group consisting of organic dicarboxylic acids and organic tricarboxylic acids.

[0056] Accordingly, preferred embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one acidifying agent, wherein the at least one acidifying agent is selected from the group comprising or comprising organic dicarboxylic acids and organic tricarboxylic acids.

[0057] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein the at least one excipient is an acidifying agent, wherein the at least one acidifying agent is selected from or comprises oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanediic acid), or glutamic acid. Preferably, at least one acidifying agent 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 (hexanediic acid), or glutamic acid. More preferably, at least one acidifying agent is selected from the group consisting of or including oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanediic acid), or glutamic acid. Even more preferably, at least one acidifying agent 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 (hexanediic acid), or glutamic acid.

[0058] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3 The present invention relates to a systemic formulation comprising or comprising -ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one acidifying agent, wherein the at least one acidifying agent is selected from the group comprising or comprising oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid (hexanediic acid), or glutamic acid.

[0059] A more preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate and at least one excipient, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein the at least one excipient is an acidifying agent, and the acidifying agent is adipic acid, fumaric acid, or glutaric acid.

[0060] A particularly preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate and at least one excipient, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein the at least one excipient is an acidifying agent, and wherein the acidifying agent is adipic acid.

[0061] Particularly preferred embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one acidifying agent, wherein the at least one acidifying agent is adipic acid.

[0062] Particularly preferred embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and adipic acid.

[0063] The drug solution, after passing through the stomach, is transferred to the duodenum. This passage is associated with an increase in pH from approximately 2 to approximately 6, at least under fasting conditions. The drug dose must remain in the solution; that is, the drug should not precipitate. This effect can be achieved by the addition of a polymer precipitation inhibitor. Thus, polymer precipitation inhibitors function as crystallization inhibitors, inhibiting the crystallization of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts.

[0064] Polymer precipitation inhibitors are polymers capable of stabilizing the supersaturation stage of a drug. In other words, polymer precipitation inhibitors can prevent the nucleation of drug molecules, or the growth of initially formed drug particles, by coating the surface of the drug particles and thus preventing particle-to-particle interaction. This is achieved by preventing the action or by increasing the viscosity of the suspension medium. The ability of precipitation inhibitors to kinetically stabilize the supersaturated state of a drug is thought to be due to intermolecular interactions between the drug and the polymer in solution (e.g., via hydrogen bonding or hydrophobic interactions), the polymer's ability to sterically interfere with the crystallization process, or an increase in the viscosity of the suspension medium, and not due to an increase in the solubility of the drug, i.e., an increase in equilibrium solubility.

[0065] The saturated solubility of the compound is low at the pH value of the small intestine (Example 10 and Figure 11). The solution is stabilized by the addition of a polymer precipitation inhibitor, which can also act as a binder. When the drug is exposed to an aqueous medium, the polymer precipitation inhibitor preferably slows down the precipitation or crystallization of the drug by complex formation.

[0066] Separately, polymer precipitation inhibitors increase the viscosity in the medium, which further enhances the effect. Therefore, the systemic formulation according to the present invention may further include a polymer precipitation inhibitor. Thus, the excipient can be a polymer precipitation inhibitor.

[0067] The term "polymer precipitation inhibitor" refers to a substance that slows down the precipitation or crystallization of a drug. "Polymer precipitation inhibitors" include cellulose derivatives, starch derivatives, dextran / dextrin derivatives, polyether derivatives, polyvinyl derivatives, polyacrylic acid derivatives, and polyamine derivatives, polysulfonic acid derivatives, and combinations thereof.

[0068] In some embodiments, the "polymer precipitation inhibitor" is This includes, but is 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 hypromellose), L-hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC or hypromellose), carboxymethyl hydroxyethylcellulose (CMHEC), sodium carboxymethyl hydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), and hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), as well as other cellulose derivatives. Starch derivatives including, but not limited to, hydroxyethyl starch, hydroxypropyl starch (HPS), and pregelatinized starch, Dextran / dextrin derivatives include, but are not limited to, cyclodextran (i.e., cycloisomalto-heptaose (CI-7), cycloisomalto-octaose (CI-8), cycloisomalto-nonaose (CI-9)), hydroxypropyl dextran, maltodextrin, α- / β- / γ-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HPβCD), sulfobutyl ether-β-cyclodextrin sodium salt, methylated-β-cyclodextrin, and 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) Polyether derivatives including, but not limited to, hydroxylated (PEO-PPO-PEO, poloxamer), such as poloxamer 188 and poloxamer 407, Polyvinyl derivatives include, but are not limited to, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(co)-polyvinyl acetate (PVPVA), and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®). Polyacrylic acid derivatives include, but are not limited to, poly(acrylic acid) (PAA), poly(acrylamide / acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid / methyl methacrylate), and poly(methacrylic acid / ethyl acrylate). Polyamine derivatives include, but are not limited to, polyethyleneimine (PEI), polyallylamine hydrogen chloride, polydiallyldimethylammonium chloride, and poly(2-ethyl-2-oxazoline). Polysulfonic acid derivatives, including but not limited to polystyrene sulfonic acid (PSSA), and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0069] Preferably, the "polymer precipitation inhibitor" is 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 hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropylmethylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), hydroxyethyl starch, hydroxypropyl starch (HPS), and pregelatinized starch, cyclodextran (i.e., cycloisomalto-heptaose (CI-7), cycloisomalto-octaose (CI-8), cycloisomalto-nonaose (CI-9)), hydroxypropyl dextran, maltodextrin, α- / β- / γ-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (H PβCD), sulfobutyl ether-β-cyclodextrin 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) (PEO-PPO-PEO, poloxamer), e.g., poloxamer 188 and poloxamer 407,Polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(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(meth, Acrylic acid / ethyl acrylate), polyethyleneimine (PEI), polyallylamine hydrogen chloride, polydiallyldimethylammonium chloride, poly(2-ethyl-2-oxazoline), polystyrene sulfonic acid (PSSA); and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0070] More preferably, the "polymer precipitation inhibitor" is 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 hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropylmethylcellulose Hypromellose acetate succinate (HPMCAS), 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), e.g., poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate Phthalates (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(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), and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0071] More preferably, suitable polymer precipitation inhibitors include L-hydroxypropylcellulose, hydroxypropylmethylcellulose, combinations 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 glycol graft copolymer (Soluplus®), and / or sodium carboxymethylcellulose. Even more preferably, polymer precipitation inhibitors are selected from the group comprising or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives. More preferably, the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, cellulose derivatives, and This is a combination of cellulose and cellulose derivatives.

[0072] Preferably, cellulose is microcrystalline cellulose (MCC), and cellulose derivatives include 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), carboxymethylcellulose sodium, carboxymethylethylcellulose (CMEC), and hydroxymethylcellulose. The following are selected from the group consisting of HMC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxymethylcellulose phthalate (HPMCP, hypromellose phthalate), and hydroxypropylmethylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate).

[0073] More preferably, the polymer precipitation inhibitor is selected from the group comprising or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropyl cellulose, and hydroxypropyl cellulose. Most preferably, the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-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-hydroxypropyl cellulose and hydroxypropyl cellulose acts as both a polymer precipitation inhibitor and a disintegrant, and therefore can reduce the amount of disintegrant.

[0074] The systemic formulations disclosed herein, and in particular systemic formulations for oral administration, most preferably include, as polymer precipitation inhibitors, polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0075] The systemic formulations disclosed herein, and in particular systemic formulations for oral administration, most preferably comprise at least one acidifying agent and / or at least one polymer precipitation inhibitor.

[0076] The systemic formulations disclosed herein, and in particular systemic formulations for oral administration, most preferably include adipic acid as an acidifying agent, and L-hydroxypropylcellulose, hydroxypropylcellulose, polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose as polymer precipitation inhibitors.

[0077] Therefore, embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7- The present invention relates to a systemic formulation comprising or consisting of oxohepto-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein at least one excipient is a polymer precipitation inhibitor.

[0078] Accordingly, embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one polymer precipitation inhibitor.

[0079] Preferably, the "polymer precipitation inhibitor" is This includes, but is 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 hypromellose), L-hydroxypropylcellulose, hydroxypropyl methylcellulose (HPMC or hypromellose), carboxymethyl hydroxyethylcellulose (CMHEC), sodium carboxymethyl hydroxyethylcellulose (NaCMHEC), hydroxypropyl methylcellulose phthalate (HPMCP, hypromellose phthalate), and hydroxypropyl methylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate), as well as other cellulose derivatives. Starch derivatives including, but not limited to, hydroxyethyl starch, hydroxypropyl starch (HPS), and pregelatinized starch, Dextran / dextrin derivatives include, but are not limited to, cyclodextran (i.e., cycloisomalto-heptaose (CI-7), cycloisomalto-octaose (CI-8), cycloisomalto-nonaose (CI-9)), hydroxypropyl dextran, maltodextrin, α- / β- / γ-cyclodextrin, 2-hydroxyethyl-β-cyclodextrin, 2-hydroxypropyl-β-cyclodextrin (HPβCD), sulfobutyl ether-β-cyclodextrin sodium salt, methylated-β-cyclodextrin, and 2-hydroxypropyl-γ-cyclodextrin. Polyether derivatives include, but are not limited to, polyethylene glycol (PEG), polyethylene oxide (PEO), polyether polyols, 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 include, but are not limited to, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(co)-polyvinyl acetate (PVPVA), and polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®). Polyacrylic acid derivatives include, but are not limited to, poly(acrylic acid) (PAA), poly(acrylamide / acrylic acid) (PAC-AC), polymethyl acrylate (PMA), polymethacrylic acid, poly(methacrylic acid / methyl methacrylate), and poly(methacrylic acid / ethyl acrylate). Polyamine derivatives include, but are not limited to, polyethyleneimine (PEI), polyallylamine hydrogen chloride, polydiallyldimethylammonium chloride, and poly(2-ethyl-2-oxazoline). Polystyrene sulfonic acid (PSSA), including but not limited to polysulfonic acid derivatives; and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0080] More preferably, the "polymer precipitation inhibitor" is 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 hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), hydroxypropylmethylcellulose Hypromellose acetate succinate (HPMCAS), 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), e.g., poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate Phthalates (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(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), and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0081] Preferred embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is a polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives.

[0082] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-ox The present invention relates to a systemic formulation comprising or comprising sohepto-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, and at least one polymer precipitation inhibitor selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives.

[0083] Preferably, cellulose is microcrystalline cellulose (MCC), and cellulose derivatives include 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), carboxymethylcellulose sodium, carboxymethylethylcellulose (CMEC), and hydroxymethylcellulose (H The following are selected from the group consisting of MC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC or hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), carboxymethylhydroxyethylcellulose (CMHEC), sodium carboxymethylhydroxyethylcellulose (NaCMHEC), hydroxypropylmethylcellulose phthalate (HPMCP, hypromellose phthalate), and hydroxypropylmethylcellulose acetate succinate (HPMCAS, hypromellose acetate succinate).

[0084] Embodiments of the present invention thus relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is a polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, and / or hydroxypropylcellulose.

[0085] Embodiments of the present invention therefore relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one polymer precipitation inhibitor selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, and / or hydroxypropylcellulose.

[0086] Embodiments of the present invention therefore include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, as well as polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Solplus(S This relates to systemic formulations containing or comprising oluplus (registered trademark), L-hydroxypropylcellulose, and / or hydroxypropylcellulose.

[0087] The systemic formulation according to the present invention may contain a binder. Therefore, the excipient can be a binder. A binder is characterized as a substance that binds or "adheres" powders to each other, and consequently functions as an "adhesive" in the formulation. In other words, a binder is a substance that holds or attracts other materials together, and the whole is held together mechanically or chemically by adhesion or aggregation. Suitable binders include sugars, such as sucrose; polysaccharides, such as xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice, and potato, as well as pre-aggregated (modified) starches and sodium starch glycolate derived from wheat, corn, rice, and potato; natural gums, such as acacia gum, gelatin, tragacanth; seaweed derivatives, such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose or cellulose derivatives, such as hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone (crospovidone), particularly povidone K25. Preferably, the binder is a polymer, more preferably a gel-forming polymer, and even more preferably cellulose or a cellulose derivative, even more preferably L-hydroxypropylcellulose, and most preferably a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0088] Hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) ether of cellulose. It may contain 0.6% or less silica or other suitable anticoagulants. Hydroxypropyl cellulose is commercially available in numerous different grades with varying solution viscosities. Its molecular weight ranges from 50,000 to 1,250,000. Hydroxypropyl cellulose is partially O-(2-hydroxypropylated)cellulose. Hydroxypropyl cellulose contains 53.4% ​​to 80.5% hydroxypropoxy groups based on the dry material. The average grade in polymerization ranges from 200 to 300. The molar grade in substitution is approximately 4.

[0089] Low-substituted hydroxypropyl cellulose (L-HPC or LHPC) is a low-substituted poly(hydroxypropyl) ether of cellulose. Low-substituted hydroxypropyl cellulose (L-HPC or LHPC) is commercially available in numerous different grades with varying particle sizes and substitution levels.

[0090] Low-substituted hydroxypropyl cellulose contains 5% to 16% hydroxypropoxy groups on a dry basis. The molar grade of substitution is <1. In particular, low-substituted hydroxypropyl cellulose is low-substituted O-(2-hydroxypropylated) cellulose and contains 5.0% to 16.0% or less hydroxypropoxy groups (-OCH2CHOHCH3) on a dry basis.

[0091] Low-substituted hydroxypropyl cellulose is low-substituted O-(2-hydroxypropylated) cellulose, and on a dry basis contains 5.0% to 16.0% or less of hydroxypropoxy groups (-OCH2CHOHCH3).

[0092] "Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus (registered trademark))" has the following chemical structure:

[0093] [ka] It has.

[0094] "Povidone" is used synonymously with polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone consists of a linear polymer of 1-ethenylpyrrolidine-2-one. Various types of polyvinylpyrrolidone are characterized by the viscosity of the polyvinylpyrrolidone solution, expressed by the K value. Polyvinylpyrrolidone exists as a white to yellowish-white powder or flake and is readily soluble in water. The K value is a common classification in the plastics industry and is directly related to the average molar mass of the polymer. This makes it possible to indirectly estimate the degree of polymerization, and therefore the chain length, from the K value. 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), and is between 28,000 g / mol(Da) and 34,000 g / mol(Da).

[0095] Accordingly, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein at least one excipient is a binder.

[0096] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder.

[0097] Therefore, a preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-( The present invention relates to a systemic formulation comprising or consisting of 2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein the at least one excipient is a binder, and the binder is polyvinylpyrrolidone.

[0098] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one polyvinylpyrrolidone.

[0099] Accordingly, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein the at least one excipient is a binder, wherein the binder is polyvinylpyrrolidone, wherein polyvinylpyrrolidone is povidone K25.

[0100] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and povidone K25.

[0101] Furthermore, the systemic formulation according to the present invention may include a binder and / or a polymer precipitation inhibitor. Accordingly, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising binders and polymer precipitation inhibitors.

[0102] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder and / or at least one polymer precipitation inhibitor.

[0103] Therefore, a preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide The present invention relates to a systemic formulation comprising or consisting of )-7-oxohepto-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 polymer precipitation inhibitor. Preferably, at least one excipient functions simultaneously as both a binder and a polymer precipitation inhibitor. Therefore, at least one excipient is both a binder and a polymer precipitation inhibitor.

[0104] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, as well as a binder and at least one compound that is a polymer precipitation inhibitor.

[0105] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one binder, and at least one polymer precipitation inhibitor.

[0106] Preferably, the "binder" is selected from the group comprising or consisting of sugars, such as sucrose; polysaccharides, such as xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice, and potatoes, as well as pre-aggregated (modified) starches, sodium starch glycolate, derived from wheat, corn, rice, and potatoes; natural gums, such as acacia gum, gelatin, and tragacanth; seaweed derivatives, such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose or cellulose derivatives, such as hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone (crospovidone), particularly povidone K25. "Polymer precipitation inhibitors" include 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 hypromellose), L-hydroxypropylcellulose, hydroxypropylmethylcellulose (HPMC or hypromellose), and carboxymethylhydroxyethylcellulose (CMHE). C) Carboxymethyl hydroxyethylcellulose sodium (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) (PEO-PPO-PEO, poloxamer), e.g., poloxamer 188 and poloxamer 407, polyvinyl alcohol (PVA), polyvinyl acetate phthalate (PVAP), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone-co(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), and A combination of at least two of the above polymer precipitation inhibitors, Selected from the group that includes or consists of.

[0107] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising binders and polymer precipitation inhibitors, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, cellulose derivatives, combinations of cellulose and derivatives, or combinations of cellulose derivatives.

[0108] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder and / or at least one polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, cellulose derivatives, combinations of cellulose and derivatives, or combinations of cellulose derivatives.

[0109] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising binders and polymer precipitation inhibitors, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0110] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder and / or at least one polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-poly The material is ethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0111] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-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 comprising or comprising binders and polymer precipitation inhibitors, wherein The remer precipitation inhibitors are polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination with L-hydroxypropylcellulose, where the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, and / or polyvinylpyrrolidone.

[0112] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one polymer precipitation inhibitor selected from the group comprising or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, and hydroxypropylcellulose, and at least one binder selected from L-hydroxypropylcellulose, hydroxypropylcellulose, and hydroxypropylcellulose and / or polyvinylpyrrolidone.

[0113] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein at least one excipient is a binder and / or at least one excipient The agent is a polymer precipitation inhibitor, where the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, cellulose derivatives, combinations of cellulose and cellulose derivatives, or combinations of cellulose derivatives; and the binder is cellulose, cellulose derivatives, combinations of cellulose and derivatives, or combinations of cellulose derivatives, and / or povidone K25.

[0114] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one binder and / or at least one polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is The binder is polyvinyl alcohol (PVA), polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, cellulose derivatives, combinations of cellulose and derivatives, or combinations of cellulose derivatives, and the binder is cellulose, cellulose derivatives, combinations of cellulose and derivatives, or combinations of cellulose derivatives, and / or povidone K25.

[0115] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-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 polymer precipitation inhibitor. Here, the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose, where the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, and / or povidone K25.

[0116] Another preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder and / or at least one polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose, wherein the binder is L-hydroxypropylcellulose, hydroxypropylcellulose, a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, and / or povidone K25.

[0117] Another preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein at least one excipient is a binder, and / or at least one excipient is a polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, wherein the binder is povidone K25.

[0118] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethyl b) The present invention relates to a systemic formulation comprising or comprising tylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one binder and / or at least a polymer precipitation inhibitor, wherein the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, wherein the binder is povidone K25.

[0119] Positive data from pharmacokinetic studies in humans support the high bioavailability of compound (I). This high bioavailability must be understood in comparison to previously conducted animal studies.

[0120] STAM-mouse model and UUO mouse model studies demonstrate the antifibrotic effects on the liver and kidney achieved by the administration of systemic formulations containing compounds of formula (I). Therefore, systemically administered drugs of formula (I) exhibit high antifibrotic activity at target sites, thereby demonstrating systemic bioavailability. Consequently, administration of oral formulations containing drugs of formula (I) exhibits high antifibrotic activity at target sites, thus leading to systemic availability (bioavailability), i.e., the drug is absorbed in target tissues.

[0121] The addition of an acidifying agent ensures the complete dissolution of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate in the stomach, but the pH in the small intestine increases from 2 to 6, and therefore the drug may precipitate before being absorbed by the small intestine. To ensure the complete dissolution of the compound in the small intestine, the formulation according to the present invention preferably includes an acidifying agent and / or a polymer precipitation inhibitor. Furthermore, in Example 9, it was possible to demonstrate that a dose of only 20 mg in humans is sufficient to achieve the drug concentration in plasma and therefore sufficient to achieve systemic availability.

[0122] Pharmacokinetic studies have shown that (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate is absorbed in the small intestine, and low doses of 20 mg to 50 mg are required to achieve therapeutically effective drug concentrations in humans (Example 7, Figure 6). Furthermore, antifibrotic effects can already be achieved at a human dose of 20 mg (Example 9 and Figure 9).

[0123] Furthermore, no off-target effects were observed. This is particularly surprising given that, as mentioned earlier, TG2 is ubiquitous in almost all cell types and cell compartments, is present on the cell surface, is secreted into the extracellular matrix, and is found in various organs. Therefore, it can be assumed that off-target effects are most likely.

[0124] Therefore, the systemic formulation according to the present invention may contain an acidifying agent and / or a polymer precipitation inhibitor. Preferably, the systemic formulation comprises an acidifying agent and a polymer precipitation inhibitor.

[0125] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising a solvate, hydrate, or pharmaceutically acceptable salt thereof, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising acidifying agents and polymer precipitation inhibitors.

[0126] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, and at least one polymer precipitation inhibitor.

[0127] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent selected from adipic acid, fumaric acid, and glutaric acid, and at least one polymer precipitation inhibitor.

[0128] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and at least one polymer precipitation inhibitor.

[0129] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one excipient, wherein at least one The excipient is selected from the group comprising or consisting of an acidifying agent and a polymer precipitation inhibitor, wherein the acidifying agent is selected from the group comprising or consisting of adipic acid, fumaric acid, and glutaric acid, and the polymer precipitation inhibitor is selected from the group comprising or consisting of polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives.

[0130] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising an acidifying agent and a polymer precipitation inhibitor, wherein the acidifying agent is adipic acid, and the polymer precipitation inhibitor is selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives.

[0131] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one acidifying agent and at least one polymer precipitation inhibitor, wherein the acidifying agent is adipic acid, and the polymer precipitation inhibitor is selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), cellulose, and cellulose derivatives.

[0132] Accordingly, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, and at least one polymer precipitation inhibitor selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, and hydroxypropylcellulose.

[0133] Accordingly, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and at least one polymer precipitation inhibitor selected from the group comprising or comprising polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, and hydroxypropylcellulose.

[0134] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising an acidifying agent and a polymer precipitation inhibitor, wherein the acidifying agent is adipic acid, and the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0135] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or drug The subject is a systemic formulation comprising or comprising a scientifically acceptable salt and at least one acidifying agent and / or at least one polymer precipitation inhibitor, wherein the acidifying agent is adipic acid, and the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose.

[0136] A systemic preparation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein the systemic preparation further comprises at least one excipient. Here, at least one excipient is selected from the group comprising or comprising an acidifying agent and a polymer precipitation inhibitor, wherein the acidifying agent is selected from the group comprising 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, or glutamic acid, and organic tricarboxylic acids such as citric acid or sodium hydrogen citrate.

[0137] A systemic preparation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein the systemic preparation further comprises at least one excipient, wherein at least one excipient is selected from the group comprising an acidifying agent and a binder, wherein the acidifying agent is 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 organic tricarboxylic acid such as citric acid or sodium hydrogen citrate. The binder is selected from the group consisting of, for example, sugars such as sucrose; polysaccharides such as xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice, and potatoes, as well as pre-aggregated starches derived from wheat, corn, rice, and potatoes, sodium starch glycolate; polyacrylic acid; natural gums such as acacia gum, gelatin, tragacanth; seaweed derivatives such as alginic acid, sodium alginate, and calcium ammonium alginate; cellulose or cellulose derivatives such as hydroxypropylcellulose, L-hydroxypropylcellulose, methylcellulose, and sodium carboxymethylcellulose, and hydroxypropylmethylcellulose, or polyvinylpyrrolidone.

[0138] The systemic formulation according to the present invention may include an acidifying agent, a polymer precipitation inhibitor, and / or a binder. Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising acidifying agents, polymer precipitation inhibitors, and binders.

[0139] A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-eth The subject matter concerns systemic formulations comprising or comprising: (butylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, at least one polymer precipitation inhibitor, and at least one binder.

[0140] A more preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, at least one acidifying agent, at least one acidifying agent, at least one polymer precipitation inhibitor, and at least one binder. The present invention relates to systemic formulations containing or comprising the following, where the acidifying agent is adipic acid, and the polymer precipitation inhibitor is polyvinyl alcohol (PVA), polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), L-hydroxypropylcellulose, hydroxypropylcellulose, or a combination of L-hydroxypropylcellulose and hydroxypropylcellulose, where the binder is polyvinylpyrrolidone.

[0141] The systemic formulation according to the present invention may contain a disintegrant. Therefore, excipients can be disintegrants. The term “disintegrant” refers to a material added to a composition to support the disintegration of the formulation and the release of the active pharmaceutical ingredient. Suitable disintegrants include starch, modified starch soluble in cold water, e.g., sodium carboxymethyl starch; cellulose derivatives, e.g., methylcellulose and sodium carboxymethylcellulose; microcrystalline cellulose and cross-linked microcrystalline cellulose, e.g., sodium croscarmellose; alginates, e.g., alginic acid, sodium alginate; clays, e.g., bentonite; and effervescent mixtures; and effervescent compounds, e.g., citric acid, tartaric acid, sodium citrate, disodium hydrogen citrate, monosodium citrate, sodium bicarbonate and / or potassium bicarbonate combinations that react in the presence of water to produce carbon dioxide. Preferably, the disintegrant is sodium croscarmellose.

[0142] Microcrystalline cellulose is purified and partially depolymerized cellulose, resulting in a white, odorless, and tasteless crystalline powder composed of porous particles. It is produced by treating alpha cellulose, obtained as pulp from fibrous plant materials, with mineral acids. Several different grades of microcrystalline cellulose are commercially available, differing in production method, particle size, moisture content, flowability, and other physical properties. Generally, larger particle size grades offer better flowability. Low moisture grades are used with moisture-sensitive materials. High-density grades provide improved flowability.

[0143] The microcrystalline cellulose used herein may have a nominal average particle size of 100 μm and a moisture content of ≤5.0%. Accordingly, embodiments of the present invention relate to systemic formulations comprising or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is a disintegrant.

[0144] Accordingly, embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one disintegrant.

[0145] The systemic formulation according to the present invention may contain an acidifying agent, a binder / polymer precipitation inhibitor, and / or a disintegrant. Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, and disintegrants.

[0146] The systemic formulation according to the present invention may contain a lubricant / flow enhancer. Therefore, the excipient can be a lubricant / flow enhancer. The lubricant / flow enhancer is a material that prevents solidification, improves the flow properties of the granules, and thus makes the flow smooth and uniform, reduces friction between surfaces in direct contact, and allows tablets, granules, etc., to be released from a mold or press after compression. Suitable lubricants / flow enhancers include sodium benzoate, metal stearate salts such as magnesium stearate, calcium stearate, or potassium stearate, stearic acid, high melting point waxes, inorganic lubricants / flow enhancers such as silicon dioxide and talc, and other lubricants / flow enhancers such as sodium oleate and polyethylene glycol. Preferably, the lubricant / flow enhancer is talc or silicon dioxide. Since the lubricant / flow enhancer must be present on the surface of the granules and between the granules and parts of the apparatus, the lubricant / flow enhancer is usually added in the final step before encapsulation or compression.

[0147] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein at least one excipient is a lubricant / flow enhancer.

[0148] Therefore, preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one lubricant / flow-promoting excipient.

[0149] The systemic formulation according to the present invention may include or consist of an acidifying agent, a polymer precipitation inhibitor, a binder, and / or a lubricant / flow enhancer. A preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or drug The subject is a systemic formulation comprising or comprising a scientifically acceptable salt and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, and lubricants / flow enhancers.

[0150] Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, and lubricants / flow enhancers.

[0151] The systemic formulation according to the present invention may comprise or consist of an acidifying agent, a polymer precipitation inhibitor, a binder, a disintegrant, and / or a lubricant / flow enhancer. Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein the at least one excipient is selected from the group comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, disintegrants, and lubricants / flow enhancers.

[0152] Furthermore, the systemic formulation according to the present invention may also contain, as excipients, diluents / fillers / binders, sweeteners, flavoring agents, buffers, antioxidants, emulsifiers, solubilizers / humectants, and / or preservatives.

[0153] A suitable diluent / filler / binder is typically a substance that forms the majority of the composition or dosage form. Suitable diluents / fillers / binders include 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 mannitol. Preferably, the diluent / filler / binder is microcrystalline cellulose if the formulation is a tablet, and mannitol if the formulation is a capsule.

[0154] The addition of mannitol further improves porosity and, therefore, improves the wetting properties of the granules. Preferred embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and at least one excipient, wherein at least one excipient is a diluent / filler / binder.

[0155] The systemic formulation according to the present invention may comprise or consist of an acidifying agent, a polymer precipitation inhibitor, a binder, a disintegrant, a lubricant / flow enhancer, and / or a diluent / filler / binder.

[0156] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino The present invention relates to a formulation comprising or comprising )-6-(1-methyl-1H-imidazole-5-carboxamide)-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 comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, disintegrants, lubricants / flow enhancers, and / or diluents / fillers / binders.

[0157] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, at least one polymer precipitation inhibitor, at least one binder, at least one disintegrant, at least one lubricant / flow enhancer, and at least one diluent / filler / binder.

[0158] Preferred formulations are provided in an administerable form suitable for oral administration, such as tablets, for example, uncoated tablets, coated tablets, effervescent tablets, soluble tablets, chewable tablets, oral lyophilized products, lozenges, pastilles, compressed lozenges, sublingual tablets, oral tablets, granules, effervescent granules, and capsules. More preferably, oral formulations are tablets or capsules. Uncoated tablets, coated tablets, and capsules are most preferably hard or soft pharmaceutical formulations.

[0159] Embodiments of the present invention relate to systemic formulations comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, wherein the systemic formulation is a tablet, coated tablet, capsule, powder, or granule.

[0160] The systemic formulation according to the present invention may include other components, such as unavoidable impurities and capsule components including capsule colorants. Furthermore, in tablets, colorants may be present as other components.

[0161] Furthermore, the ingredients used to coat the tablets are also included in the term "other ingredients." The capsule shell may contain a coloring agent. As used herein, the term "coloring agent" includes pigments such as white pigments. The coloring agent may, among other things, be iron oxide, particularly iron(III) oxide, iron(II,III) oxide, or hydrated ferric oxide, or titanium dioxide.

[0162] "Tablet" means a compressed solid dosage form containing at least one active pharmaceutical ingredient together with appropriate excipients. Tablets can be produced by compressing a mixture or granules obtained by wet granulation, dry granulation, or compression, as known to those skilled in the art.

[0163] The term "capsule" refers to a special container or shell composed of methylcellulose, polyvinyl alcohol, or gelatin, or modified gelatin, or starch, that can encapsulate an active ingredient. Typically, hard-shelled capsules are prepared from hydroxypropyl methylcellulose or a mixture of porcine bone and skin gelatin, which has relatively high gel strength. The capsule shell contains small amounts of colorants, opacifiers, softeners, and preservatives. It is possible to do this. The "soft-shelled capsule" contains gelatin as the basic polymer, one or more high doses of softeners, such as glycerol or sorbitol, and water. Typically, the amount of softener 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% by weight of the capsule shell.

[0164] The capsule shell may include gelatin, hydroxypropyl methylcellulose (HMPC), polysaccharides such as starch and carrageenan; and / or synthetic polymers such as polyvinyl alcohol copolymers. Furthermore, the capsule shell may contain colorants. As used herein, the term "colorant" includes pigments such as white pigments. Colorants may, among other things, be iron oxides, particularly iron(III) oxide, iron(II,III) oxide, or hydrated ferric oxide, titanium dioxide, natural dyes, azos, and xanthan compounds. Furthermore, the capsule shell may contain preservatives such as p-hydroxybenzoic acid esters, or methods to improve flavor such as ethyl vanillin. Furthermore, the capsule shell may contain surfactants such as sodium lauryl sulfate.

[0165] For compositional purposes, "powder" refers to a powder mixture / blend containing an active ingredient and appropriate excipients that can be suspended in water or juice before use. Spherical granules are also called pellets or beads.

[0166] "Granules" refer to dry, solid particles. Each particle represents an aggregate of powder particles. Drug particles are processed by packaging or embedding, but the coating method is related to the dosage form itself. The core of a tablet, sugar-coated tablet, or capsule is coated with a coating layer, where excipients such as cellulose derivatives, cellulose ethers such as hydroxypropyl methylcellulose (HMPC), synthetic polymers, shellac, corn protein zein, or other polysaccharides, as well as anionic copolymers of methacrylic acid and methyl methacrylate. The coating may further contain colorants such as titanium dioxide, iron(III) oxide, iron(II,III) oxide or hydrated ferric oxide, lactose monohydrate, and / or carnauba wax. Furthermore, capsules may be coated.

[0167] Sustained-release formulations are known in the latest technologies for providing a controlled release rate of any one or more components or active ingredients to optimize therapeutic effects, i.e., inhibitory activity. The pharmacologically optimal concentration is guaranteed for a specific time over the duration of the effect in a single dose. Dosage forms suitable for sustained release include layered tablets in the form of tablets or capsules containing a layer having a varying degradation rate, or a controlled-release polymer matrix impregnated with the active ingredient, and an impregnated or encapsulated porous polymer matrix. Sustained-release formulations would hinder the rapid release of the compound. Here, high concentrations of the drug are desired to be rapidly released to the target site after administration. Consequently, since preliminary results show that the formulation cannot provide the high drug concentrations required according to the present invention, sustained-release formulations are undesirable and should be avoided in practice for the purposes of the present invention.

[0168] The systemic formulation according to the present invention may be in the form of a capsule or a tablet, i.e., the activator and excipients may be filled into the capsule. Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, It is a systemic preparation consisting of or , where the systemic preparation is in the form of a capsule or tablet.

[0169] A preferred embodiment of the present invention is a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising acidifying agents and polymer precipitation inhibitors, and the systemic formulation is in the form of a capsule or tablet.

[0170] A preferred embodiment of the present invention is a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, at least one acidifying agent, and at least one polymer precipitation inhibitor, wherein the systemic formulation is in the form of a capsule or tablet.

[0171] Another preferred embodiment of the present invention is a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising acidifying agents, polymer precipitation inhibitors, and binders, and wherein the systemic formulation is in the form of a capsule or tablet.

[0172] Another preferred embodiment of the present invention is a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, at least one polymer precipitation inhibitor, and at least one binder, wherein the systemic formulation is in the form of a capsule or a tablet.

[0173] Another preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising acidifying agents, polymer precipitation inhibitors, binders, disintegrants, and lubricants / flow enhancers, wherein the systemic formulation is in the form of a capsule or tablet.

[0174] Other preferred embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or This relates to a systemic formulation comprising or comprising a pharmaceutically acceptable salt, at least one acidifying agent, at least one polymer precipitation inhibitor, at least one binder, at least one disintegrant, and at least one lubricant / flow enhancer, wherein the systemic formulation is in the form of a capsule or a tablet.

[0175] Another preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 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 comprising or comprising acidifying agents, polymer precipitation inhibitors, diluents / fillers / binders, disintegrants, lubricants / flow enhancers, and diluents / fillers / binders, wherein the systemic formulation is in the form of a capsule or a tablet.

[0176] Another preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, at least one acidifying agent, at least one polymer precipitation inhibitor, at least one binder, at least one disintegrant, at least one lubricant / flow enhancer, and at least one diluent / filler / binder, wherein the systemic formulation is in the form of a capsule or tablet.

[0177] Preferred pharmaceutical formulations are for oral administration. Therefore, preferred pharmaceutical formulations are systemic formulations in the form of enteral or parenteral formulations for oral administration. As a result, capsules and tablets in particular are most preferably enteral or parenteral formulations for oral administration, and in particular capsules and tablets that ensure high drug concentration by ensuring the rapid release of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate. Therefore, sustained-release formulations are not suitable and should not be used for the purposes of the present invention in practice.

[0178] Furthermore, an orally administered pharmaceutical formulation containing adipic acid is preferred. More preferably, a systemic formulation in the form of an orally administered enteral or parenteral formulation containing adipic acid. Most preferably, an orally administered capsule or tablet containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and adipic acid.

[0179] Furthermore, specific PSD (particle size distribution) and / or PSR (particle size range) can be adapted to further improve the performance of the formulation. Therefore, embodiments of the present invention are given by formula (I):

[0180] [ka] The subject is a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or a solvate, hydrate, or pharmaceutically acceptable salt of formula (I), wherein the particles of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate have a particle size range of 0.1 μm to 100 μm.

[0181] The particle size of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, is preferably in the range of 0.1 μm to 100 μm, more preferably in the range of 0.5 μm to 50 μm, and more preferably in the range of 1.0 μm to 20 μm. Therefore, the particle size range (PSR) of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, is 0.1 μm to 100 μm, 0.5 μm to 50 μm, or 1.0 μm to 20 μm. Preferably, the particle size of the drug according to formula (I) is ≤10 μm.

[0182] Other preferred embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and L-Hypermethylamino acid. A systemic preparation comprising or including droxypropylcellulose, wherein the (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size range of 0.1 μm to 100 μm.

[0183] Therefore, embodiments of the present invention are given by formula (I):

[0184] [ka] The subject is a systemic preparation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate, or pharmaceutically acceptable salt of formula (I), where (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6- The particles of (1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate have a particle size distribution defined by d(0.95) ≤ 25 μm, where (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts are preferably micronized.

[0185] Furthermore, (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, are preferably d(0.1) 0.1 μm to 5 μm. The micrometers are characterized by m, d(0.5) 0.3 μm to 10 μm, d(0.95) 3 μm to 25 μm, more preferably d(0.1) 0.2 μm to 3 μm, d(0.5) 0.4 μm to 7.5 μm, and d(0.95) 2 μm to 15 μm, and most preferably d(0.1) 0.3 μm to 3 μm, d(0.5) 0.5 μm to 5 μm, and d(0.95) 1 μm to 10 μm.

[0186] The particle size distribution is measured by laser diffraction (Malvern analysis, using samples dispersed in n-hexane and sorbitan monooleate). Therefore, the laser light is scattered in a particle size-dependent manner. The diffraction pattern is derived from the angle-dependent scattered light intensity, allowing for the calculation of particle size.

[0187] The parameter d(0.1) refers to the diameter of particles that, when 10% of the total volume of a sample is analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate), have a diameter smaller than the indicated value or range of values. Therefore, d(0.1) = 0.1 μm to 5 μm means that the upper limit of the particle size range defining 10% of the smallest particles in the sample is between 0.1 μm and 5 μm. Thus, 10% of all particles have a particle size of d(0.1) or less, and in this case, 10% of all particles have a maximum size between 0.1 μm and 5 μm.

[0188] Consequently, the parameter d(0.5) refers to the diameter of particles that, when 50% of the total volume of the sample is analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate), have a diameter smaller than the indicated value or range of values. Therefore, d(0.5) = 0.3 μm to 10 μm means that the upper limit of the particle size range defining 50% of the smallest particles in the sample is between 0.3 μm and 10 μm. Thus, 50% of all particles have a particle size of d(0.5) or less, and in this case, 50% of all particles have a maximum size between 0.3 μm and 10 μm.

[0189] Consequently, the parameter d(0.95) refers to the diameter of particles that, when 95% of the total volume of particles in the sample are analyzed by laser diffraction (Malvern analysis, sample dispersed in n-hexane and sorbitan monooleate), have a diameter smaller than the indicated value or range of values. Therefore, d(0.95) = 3 μm to 25 μm means that the upper limit of the particle size range defining 95% of the smallest particles in the sample is between 3 μm and 25 μm. Thus, 95% of all particles have a particle size of d(0.95) or less, and in this case, 95% of all particles have a maximum size between 3 μm and 25 μm.

[0190] Other embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and L-hydroxyl The subject is a systemic formulation containing cypropylcellulose, where (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by d(0.95) ≤ 25 μm.

[0191] A preferred embodiment of the present invention relates to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, wherein (S,E The )-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by d(0.1) 0.1 μm to 5 μm, d(0.5) 0.3 μm to 10 μm, and d(0.95) 3 μm to 25 μm.

[0192] A more preferred embodiment of the present invention comprises (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and L-hydroxypropylcellulose. A systemic preparation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles, d(0.1) from 0.1 μm to 5 μm, d(0.5) from 0.3 μm to 10 μm, and d(0.95) from 3 μm to 25 μm. It has a particle size distribution defined as follows.

[0193] A more preferred embodiment of the present invention comprises or omits (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, and L-hydroxypropylcellulose. This is a systemic formulation in which (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by d(0.1) 0.2 μm to 3 μm, d(0.5) 0.4 μm to 7.5 μm, and d(0.95) 2 μm to 15 μm.

[0194] A more preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose, croscarmellose sodium, and talc. A systemic formulation comprising or comprising, where (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by d(0.1) 0.1 μm to 5 μm, d(0.5) 0.3 μm to 10 μm, and d(0.95) 3 μm to 25 μm.

[0195] Particularly preferred embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose, croscarmellose sodium, talc, gelatin, and A systemic preparation comprising or consisting of titanium dioxide, wherein (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate has a particle size distribution defined by d(0.1) 0.1 μm to 5 μm, d(0.5) 0.3 μm to 10 μm, and d(0.95) 3 μm to 25 μm.

[0196] Other particularly preferred embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose, povidone K25, croscarmellose sodium, and microcrystalline cellulose. The present invention relates to a systemic preparation comprising or comprising crystalline cellulose and silicon dioxide, wherein (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate is defined by d(0.1) 0.1 μm to 5 μm, d(0.5) 0.3 μm to 10 μm, and d(0.95) 3 μm to 25 μm. It has a defined particle size distribution.

[0197] Therefore, embodiments of the present invention are given by formula (I):

[0198] [ka] The subject is a systemic preparation containing (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate, or pharmaceutically acceptable salt of formula (I), where, (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by a particle size range of 0.1 μm to 100 μm and d(0.95) ≤ 25 μm.

[0199] Therefore, preferably, a systemic preparation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, where (S,E)- Methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, are in the form of particles having a particle size distribution defined by d(0.95) ≤ 25 μm.

[0200] A preferred embodiment of the present invention comprises (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose. A systemic preparation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles having a particle size range of 0.1 μm to 100 μm and a particle size distribution defined by d(0.95) ≤ 25 μm.

[0201] A more preferred embodiment of the present invention is (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine A systemic preparation comprising or consisting of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, adipic acid, L-hydroxypropylcellulose, hydroxypropylcellulose, mannitol, croscarmellose sodium, and talc, wherein the (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by a particle size range of 0.1 μm to 100 μm and d(0.95) ≤ 25 μm.

[0202] Particularly preferred embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose, hydroxypropylcellulose, mannitol, croscarmellol A systemic preparation comprising or consisting of sodium methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles having a particle size distribution defined by a particle size range of 0.1 μm to 100 μm and d(0.95) ≤ 25 μm.

[0203] In addition to the present invention, particularly preferred embodiments include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, adipic acid, L-hydroxypropylcellulose, povidone K25, and croscarmellose sodium. The present invention relates to a systemic formulation comprising or consisting of microcrystalline cellulose and silicon dioxide, wherein the (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size range of 0.1 μm to 100 μm and a particle size distribution defined by d(0.95) ≤ 25 μm.

[0204] The systemic formulation contains (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its 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, and even more preferably at least 5 mg per formulation. mg, more preferably 0.01 mg to 1000 mg, more preferably 0.05 mg to 900 mg, more preferably 0.10 mg to 800 mg, more preferably 0.2 mg to 700 mg, more preferably 0.3 mg to 600 mg, more preferably 0.4 mg to 500 mg, more preferably 0.5 mg to 500 mg, more preferably 0.6 mg to 450 mg, more preferably 0.7 mg to 400 mg, more preferably 0.8 mg to 375 mg, more preferably 0.9 mg to 350 mg, more preferably 1.0 mg to 300 mg, more preferably 1.25 mg to 300 mg, and even more preferably It may contain an amount of 1.5 mg to 275 mg, more preferably 1.75 mg to 250 mg, more preferably 2.0 mg to 225 mg, more preferably 2.25 mg to 220 mg, more preferably 2.5 mg to 220 mg, more preferably 2.75 mg to 215 mg, more preferably 3.0 mg to 210 mg, more preferably 3.75 mg to 205 mg, more preferably 4.0 mg to 205 mg, 4.5 mg to 200 mg, and most preferably 5 mg to 200 mg.

[0205] The systemic formulation contains (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, solvate, or hydrate, in an amount from 0.1 wt% to 99 wt%, preferably 0 0.2 wt% to 90 wt%, more preferably 0.3 wt% to 85 wt%, even more preferably 0.4 wt% to 80 wt%, even more preferably 0.5 wt% to 75 wt%, even more preferably 0.6 wt% to 70 wt%, even more preferably 0.7 wt% to 65 wt%, even more preferably 0.8 wt% to 60 wt%, even more preferably 0.9 wt% to 55 wt%, and even more preferably 1 wt% to 50 wt It can be contained in amounts of %, more preferably 1 wt% to 45 wt%, more preferably 1.25 wt% to 45 wt%, more preferably 1.5 wt% to 40 wt%, more preferably 1.75 wt% to 35 wt%, more preferably 2 wt% to 34 wt%, more preferably 2.25 wt% to 33 wt%, more preferably 2.5 wt% to 32 wt%, and most preferably 2.5 wt% to 31 wt%, more preferably 2.5 wt% to 30.5 wt%, and more preferably 2.6 wt% to 30.3 wt%, more preferably 3 wt% to 30 wt%, more preferably 3.5 wt% to 29 wt%, more preferably 4 wt% to 28 wt%, more preferably 4 wt% to 27 wt%, more preferably 4.5 wt% to 27 wt%, and most preferably 5 wt% to 27 wt%. "Wt%" (weight percentage) refers to the weight percentage of the composition.

[0206] The amount of acidifying agent is 0.1 wt% to 80 wt%, preferably 0.5 wt% to 77.5 wt%, more preferably 1 wt% to 75 wt%, more preferably 1.5 wt% to 72.5 wt%, more preferably 1.5 wt% to 72.5 wt%, more preferably 2 wt% to 70 wt%, more preferably 2.5 wt% to 62.5 wt%, more preferably 3 wt% to 57.5 wt%, more preferably 3.5 wt% to 55 wt%, and even more preferably 4 wt% to 55 wt%. The range can be %, more preferably 4.5 wt% to 55 wt%, more preferably 5 wt% to 54 wt%, more preferably 5.5 wt% to 53 wt%, more preferably 6 wt% to 52 wt%, more preferably 6.5 wt% to 51 wt%, more preferably 7 wt% to 50 wt%, more preferably 8 wt% to 49 wt%, more preferably 8.5 wt% to 49 wt%, and most preferably 9 wt% to 49 wt%.

[0207] Furthermore, the amount of acidifying agent is 1.00 mg to 500 mg, more preferably 1.25 mg to 495 mg, even more preferably 1.50 mg to 490 mg, even more preferably 1.75 mg to 485 mg, even more preferably 2.00 mg to 480 mg, even more preferably 2.25 mg to 475 mg, even more preferably 2.50 mg to 470 mg, even more preferably 3.0 mg to 465 mg, even more preferably 3.25 mg to 460 mg, even more preferably 3.5 mg to 455 mg, even more preferably 3.75 mg to 450 mg, even more preferably 4.00 mg to 445 mg, even more preferably 4.25 mg to 440 mg, even more preferably 4.5 mg to 435 mg, even more preferably 4.75 mg to 430 mg, even more preferably 5.0 mg to 425 mg, even more preferably 5.25 mg to 420 mg, and even more preferably 5. The dosage can range from 5 mg to 415 mg, more preferably from 5.75 mg to 410 mg, more preferably from 6.0 mg to 410 mg, more preferably from 6.25 mg to 405 mg, more preferably from 6.5 mg to 400 mg, more preferably from 6.75 mg to 395 mg, more preferably from 7.0 mg to 390 mg, more preferably from 7.5 mg to 390 mg, more preferably from 7.75 mg to 385 mg, more preferably from 8.0 mg to 380 mg, more preferably from 8.5 mg to 375 mg, more preferably from 9 mg to 370 mg, more preferably from 9 mg to 365 mg, more preferably from 9 mg to 360 mg, more preferably from 9 mg to 350 mg, more preferably from 9 mg to 325 mg, more preferably from 9 mg to 300 mg, more preferably from 9 mg to 250 mg, more preferably from 9 mg to 200 mg, and most preferably from 9 mg to 180 mg.

[0208] Furthermore, the mass ratio of the acidifying agent to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt is 15 to 0.1 m / m, preferably 14.5 to 0.2 m / m, more preferably 14.0 to 0.3 m / m, even more preferably 13.5 to 0.4 m / m, even more preferably 13.0 to 0.5 m / m, and even more preferably 12.5 to 0.6 m / m. The range can be mm, more preferably 12.0 to 0.7 mm, more preferably 11.75 to 0.8 mm, more preferably 11.5 to 0.9 mm, more preferably 11.5 to 1.0 mm, more preferably 11.5 to 1.1 mm, more preferably 11.5 to 1.2 mm, more preferably 11.5 to 1.3 mm, more preferably 11.5 to 1.4 mm, more preferably 11.5 to 1.5 mm, more preferably 11.5 to 1.6 mm, more preferably 11.5 to 1.7 mm, and most preferably 11.5 to 1.8 mm.

[0209] The amount of polymer precipitation inhibitor can vary from 0.1 wt% to 40 wt%, preferably 0.5 wt% to 39 wt%, more preferably 1 wt% to 38 wt%, even more preferably 1.25 wt% to 38 wt%, even more preferably 1.5 wt% to 37 wt%, even more preferably 1.75 wt% to 36 wt%, even more preferably 2 wt% to 35 wt%, even more preferably 1.5 wt% to 34 wt%, even more preferably 1.6 wt% to 33 wt%, even more preferably 1.7 wt% to 32 wt%, even more preferably 1.8 wt% to 31 wt%, even more preferably 3.5 wt% to 30 wt%, even more preferably 4 wt% to 29 wt%, even more preferably 4.5 wt% to 28.5 wt%, and most preferably 5 wt% to 28.5 wt%.

[0210] Furthermore, the amount of polymer precipitation inhibitor can be in the range of 1 mg to 100 mg, preferably 1.5 mg to 95 mg, more preferably 2 mg to 92.5 mg, even more preferably 2.5 mg to 90 mg, even more preferably 3 mg to 87.5 mg, even more preferably 3.5 mg to 85 mg, even more preferably 4 mg to 82.5 mg, even more preferably 4.5 mg to 80 mg, even more preferably 5 mg to 77.5 mg, even more preferably 5.5 mg to 75 mg, 6 mg to 72.5 mg, even more preferably 6.5 mg to 70 mg, even more preferably 7 mg to 65 mg, even more preferably 7.5 mg to 62.5 mg, even more preferably 8 mg to 60 mg, even more preferably 8.5 mg to 57.5 mg, even more preferably 9 mg to 55 mg, even more preferably 9.5 mg to 52.5 mg, even more preferably 9.75 mg to 52.5 mg, and most preferably 10 mg to 50 mg.

[0211] Furthermore, the mass ratio of the polymer precipitation inhibitor to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, is 0.05 to 10 m / m, preferably 0.06 to 9.5 m / m, more preferably 0.07 to 9.00 m / m, even more preferably 0.08 to 8.50 m / m, and even more preferably 0. The range can be 0.9 to 8.00 mm, more preferably 0.1 to 7.5 mm, more preferably 0.11 to 7.25 mm, more preferably 0.12 to 7 mm, more preferably 0.13 to 6.75 mm, more preferably 0.14 to 6.5 mm, more preferably 0.15 to 6.25 mm, more preferably 0.16 to 6 mm, more preferably 0.17 to 5.75 mm, more preferably 0.18 to 5.5 mm, more preferably 0.19 to 5.25 mm, and most preferably 0.20 to 5 mm.

[0212] The amount of binder can vary from 0 wt% to 40 wt%, preferably from 0 wt% to 35 wt%, more preferably from 0 wt% to 30 wt%, even more preferably from 0 wt% to 25 wt%, even more preferably from 0 wt% to 20 wt%, even more preferably from 0 wt% to 15 wt%, even more preferably from 0 wt% to 12 wt%, and most preferably from 0 wt% to 8.5 wt%.

[0213] Furthermore, the amount of binder is 1.00 mg to 100 mg, preferably 1.50 mg to 95 mg, more preferably 2.00 mg to 92.5 mg, even more preferably 2.50 mg to 90 mg, even more preferably 3.00 mg to 87.5 mg, even more preferably 3.50 mg to 85 mg, even more preferably 4.00 mg to 82.5 mg, even more preferably 4.50 mg to 80 mg, even more preferably 5.00 mg to 77.5 mg, even more preferably 5.50 mg to 75 mg, 6.00 The range can be from mg to 72.5 mg, more preferably 6.50 mg to 70 mg, more preferably 7.00 mg to 65 mg, more preferably 7.50 mg to 62.5 mg, more preferably 8.00 mg to 60 mg, more preferably 8.50 mg to 57.5 mg, more preferably 9.00 mg to 55.0 mg, more preferably 9.50 mg to 52.5 mg, more preferably 9.75 mg to 52.5 mg, and most preferably in the range of 10 mg to 50 mg.

[0214] Furthermore, the mass ratio of the binder to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, is 0 to 10 m / m, preferably 0.05 to 9.5 m / m, more preferably 0.06 to 9.00 m / m, even more preferably 0.07 to 8.50 m / m, even more preferably 0.08 to 8.00 m / m, even more preferably 0.09 to 7.5 m / m, even more preferably 0.1 to 7.25 m / m, and even more preferably 0. 11 to 7.00 mm, more preferably 0.12 to 6.75 mm, more preferably 0.13 to 6.50 mm, more preferably 0.14 to 6.25 mm, more preferably 0.15 to 6.00 mm, more preferably 0.16 to 5.75 mm, more preferably 0.17 to 5.50 mm, more preferably 0.18 to 5.25 mm, more preferably 0.19 to 5.5 mm, more preferably 0.20 to 5 mm, more preferably 0.20 to 4.5 mm, more preferably 0.20 to 4 mm, more preferably 0.20 to 3.5 mm, more preferably 0.20 to 3 mm, and more preferably 0.20 to 2.5 mm , and more preferably in the range of 0.20 to 2 mm / m.

[0215] The amount of disintegrant can vary from 0.1 wt% to 40 wt%, preferably 1 wt% to 35 wt%, more preferably 2 wt% to 30 wt%, more preferably 2.5 wt% to 29 wt%, more preferably 3.0 wt% to 28 wt%, more preferably 3.5 wt% to 27 wt%, and most preferably 3.5 wt% to 26.5 wt%.

[0216] Furthermore, the amount of disintegrant is 0.1 mg to 150 mg, preferably 0.50 mg to 145 mg, more preferably 0.75 mg to 140 mg, even more preferably 1.00 mg to 135 mg, even more preferably 1.25 mg to 130 mg, even more preferably 1.50 mg to 125 mg, even more preferably 1.75 mg to 120 mg, even more preferably 2.00 mg to 115 mg, even more preferably 2.25 mg to 110 mg, even more preferably 2.50 mg to 105 mg, even more preferably 2.75 mg to 100 mg, even more preferably 3.00 mg to 95 mg, even more preferably 3.25 mg to 90 mg, even more preferably 3.50 mg to 85 mg, even more preferably 3.75 mg to 80 mg, and even more The amount can vary from preferably 4.00 mg to 75 mg, more preferably 4.25 mg to 70 mg, more preferably 4.50 mg to 65 mg, more preferably 4.75 mg to 60 mg, more preferably 5.00 mg to 55 mg, more preferably 5.50 mg to 50 mg, more preferably 6.00 mg to 45 mg, more preferably 6.50 mg to 42.5 mg, more preferably 7.00 mg to 40 mg, more preferably 7.50 mg to 40 mg, more preferably 8.00 mg to 40 mg, more preferably 8.50 mg to 40 mg, more preferably 9.00 mg to 40 mg, more preferably 9.50 mg to 40 mg, and most preferably 10 mg to 40 mg.

[0217] Furthermore, the mass ratio of the disintegrant to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt is 0.05 to 12 m / m, preferably 0.06 to 11.5 m / m, more preferably 0.07 to 11 m / m, even more preferably 0.08 to 10.5 m / m, and even more preferably 0 The range is 0.09 to 10 mm, more preferably 0.1 to 9.5 mm, more preferably 0.11 to 9 mm, more preferably 0.12 to 8.5 mm, more preferably 0.13 to 8 mm, more preferably 0.14 to 7.5 mm, more preferably 0.15 to 7 mm, more preferably 0.16 to 6.5 mm, more preferably 0.17 to 5.5 mm, more preferably 0.18 to 5 mm, more preferably 0.19 to 5 mm, and most preferably in the range of 0.2 to 5 mm.

[0218] The amount of lubricant / flow enhancer can be in the range of 0.1 wt% to 10 wt%, preferably more preferably 0.25 wt% to 9.5 wt%, even more preferably 0.5 wt% to 9 wt%, even more preferably 0.75 wt% to 8.5 wt%, even more preferably 1 wt% to 8 wt%, even more preferably 1.25 wt% to 7.5 wt%, even more preferably 1.5 wt% to 7 wt%, and even more preferably 1.5 wt% to 6.5 wt%.

[0219] Furthermore, the amount of lubricant / flow enhancer is 0.01 mg to 100 mg, preferably 0.05 mg to 95 mg, more preferably 0.1 mg to 90 mg, even more preferably 0.3 mg to 85 mg, even more preferably 0.4 mg to 80 mg, and even more preferably The amount can range from 0.5 mg to 0.6 mg, more preferably from 0.7 mg to 70 mg, more preferably from 0.8 mg to 65 mg, more preferably from 0.9 mg to 60 mg, more preferably from 1 mg to 55 mg, more preferably from 1.1 mg to 50 mg, more preferably from 1.2 mg to 45 mg, more preferably from 1.3 mg to 40 mg, more preferably from 1.4 mg to 35 mg, more preferably from 1.5 mg to 30 mg, more preferably from 1.6 mg to 25 mg, more preferably from 1.7 mg to 20 mg, more preferably from 1.8 mg to 20 mg, more preferably from 1.9 mg to 20 mg, more preferably from 2 mg to 20 mg, more preferably from 3 mg to 20 mg, more preferably from 4 mg to 20 mg, and most preferably, more preferably, in the range of 5 mg to 20 mg.

[0220] Furthermore, the mass ratio of the lubricant / flow enhancer to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, can be in the range of 0.05 to 2 m / m, preferably 0.06 to 1.8 m / m, more preferably 0.07 to 1.6 m / m, 0.08 to 1.4 m / m, even more preferably 0.09 to 1.3 m / m, and most preferably 0.1 to 1.2 m / m.

[0221] The amount of diluent / filler / binder in the composition can be in the range of 0 wt% to 50% wt%, preferably 1 wt% to 47.5% wt%, more preferably 1.5 wt% to 45% wt%, more preferably 2 wt% to 42.5% wt%, more preferably 2.5 to 40 wt%, more preferably 3 wt% to 38% wt%, more preferably 3.5 wt% to 38 wt%, more preferably 4 wt% to 38 wt%, more preferably 4.5 wt% to 38 wt%, and even more preferably 5 wt% to 38 wt%.

[0222] Furthermore, the amount of diluent / filler / binder is 1 mg to 290 mg, preferably 2 mg to 280 mg, more preferably 3 mg to 270 mg, even more preferably 4 mg to 260 mg, even more preferably 5 mg to 250 mg, even more preferably 6 mg to 240 mg, even more preferably 7 mg to 230 mg, even more preferably 8 mg to 220 mg, even more preferably 9 mg to 210 mg, even more preferably 10 mg to 200 mg, even more preferably 11 mg to 190 mg, even more preferably 12 mg to 180 mg, even more preferably 13 mg to 170 mg, and even more preferably The amount can be in the range of 14 mg to 160 mg, more preferably 15 mg to 150 mg, more preferably 16 mg to 140 mg, more preferably 17 mg to 130 mg, more preferably 18 mg to 120 mg, more preferably 19 mg to 110 mg, more preferably 19 mg to 100 mg, more preferably 20 mg to 90 mg, more preferably 21 mg to 80 mg, more preferably 22 mg to 70 mg, more preferably 23 mg to 60 mg, more preferably 24 mg to 55 mg, and most preferably 25 mg to 50 mg.

[0223] Furthermore, the mass ratio of the diluent / filler / binder to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt is 0 m / m to 20 m / m, more preferably 0.01 m / m to 17.5 m / m, more preferably 0.05 m / m to 15 m / m, more preferably 0.1 m / m to 0.125 m / m, and more preferably 0.15 m / m to 10 The range can be m / m, more preferably 0.175 mm to 7.5 mm, more preferably 0.2 mm to 6 mm, more preferably 0.2 mm to 5.5 mm, and more preferably 0.2 mm to 5 mm.

[0224] The amounts of other components can range from 5 wt% to 60 wt%, preferably 6 wt% to 57.5 wt%, more preferably 7 wt% to 55 wt%, even more preferably 8 wt% to 52.5 wt%, even more preferably 9 wt% to 51 wt%, and most preferably 10 wt% to 50 wt% relative to the dosage form.

[0225] Furthermore, the amounts of other components can range from 50 mg to 200 mg, preferably 55 mg to 190 mg, more preferably 60 mg to 180 mg, even more preferably 65 mg to 170 mg, even more preferably 70 mg to 160 mg, even more preferably 75 mg to 150 mg, even more preferably 80 mg to 140 mg, even more preferably 90 mg to 130 mg, even more preferably 90 mg to 120 mg, even more preferably 90 mg to 110 mg, and most preferably 90 mg to 100 mg.

[0226] Furthermore, the mass ratio of the other components to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, can be in the range of 0 to 30 m / m, preferably 0.2 to 27.5 m / m, more preferably 0.3 to 25 m / m, even more preferably 0.35 to 22.5 m / m, even more preferably 0.4 to 21 m / m, and most preferably 0.45 to 20 m / m.

[0227] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts.

[0228] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts.

[0229] Embodiments of the present invention relate to systemic formulations comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts.

[0230] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 1 wt% to 75 wt% of an acidifying agent.

[0231] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 3 wt% to 75 wt% of an acidifying agent.

[0232] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 4.5 wt% to 55 wt% of an acidifying agent.

[0233] Embodiments of the present invention relate to a systemic formulation comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 1 wt% to 75 wt% of an acidifying agent.

[0234] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 3 wt% to 75 wt% of an acidifying agent.

[0235] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 4.5 wt% to 55 wt% of an acidifying agent.

[0236] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 1 wt% to 75 wt% of an acidifying agent.

[0237] Embodiments of the present invention relate to a systemic formulation comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3 wt% to 75 wt% of an acidifying agent.

[0238] Embodiments of the present invention relate to systemic formulations comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 4.5 wt% to 55 wt% of an acidifying agent.

[0239] Embodiments of the present invention relate to a systemic formulation comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 1 wt% to 75 wt% of an acidifying agent.

[0240] Embodiments of the present invention relate to a systemic formulation comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3 wt% to 75 wt% of an acidifying agent.

[0241] Embodiments of the present invention relate to a systemic formulation comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 4.5 wt% to 55 wt% of an acidifying agent.

[0242] Preferred embodiments of the present invention relate to systemic formulations comprising, or consisting of, (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, and 1 wt% to 75 wt% adipic acid.

[0243] Preferred embodiments of the present invention relate to systemic formulations comprising, or consisting of, (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, and 3 wt% to 75 wt% adipic acid.

[0244] Preferred embodiments of the present invention relate to systemic formulations comprising, or consisting of, (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, and 4.5 wt% to 55 wt% adipic acid.

[0245] More preferred embodiments of the present invention relate to systemic formulations comprising, or consisting of, 0.1 wt% to 80 wt% (S,E)-methyl -7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, and 1 wt% to 75 wt% adipic acid.

[0246] A more preferred embodiment of the present invention relates to a systemic formulation comprising, or consisting of, 0.1 wt% to 80 wt% of (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 3 wt% to 75 wt% of adipic acid.

[0247] A more preferred embodiment of the present invention relates to a systemic formulation comprising, or consisting of, 0.1 wt% to 80 wt% of (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 4.5 wt% to 55 wt% of adipic acid.

[0248] A preferred embodiment of the present invention relates to a systemic formulation comprising, or consisting of, 0.1 wt% to 45 wt% of (S,E)-methyl 7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 1 wt% to 75 wt% of adipic acid.

[0249] A preferred embodiment of the present invention relates to a systemic formulation comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3 wt% to 75 wt% of adipic acid.

[0250] A preferred embodiment of the present invention relates to a systemic formulation comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 4.5 wt% to 55 wt% of adipic acid.

[0251] A preferred embodiment of the present invention relates to a systemic formulation comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 1 wt% to 75 wt% of adipic acid.

[0252] A preferred embodiment of the present invention is 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1 The present invention relates to a systemic preparation comprising, or comprising, 2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, and 3 wt% to 75 wt% adipic acid.

[0253] A preferred embodiment of the present invention relates to a systemic formulation comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 4.5 wt% to 55 wt% of adipic acid.

[0254] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0255] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0256] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0257] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0258] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 35 wt% of a polymer precipitation inhibitor.

[0259] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carb The present invention relates to a systemic formulation comprising or comprising xamide-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 2 wt% to 30 wt% of a polymer precipitation inhibitor.

[0260] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0261] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0262] Embodiments of the present invention relate to a systemic formulation comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0263] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0264] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0265] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0266] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable substances. Relates to a systemic formulation comprising a salt, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, or consisting of the same.

[0267] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, or consisting of the same.

[0268] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, or consisting of the same.

[0269] Embodiments of the present invention relate to a systemic formulation comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate or pharmaceutically acceptable salt, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, or consisting of the same.

[0270] Preferred embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0271] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0272] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0273] A preferred embodiment of the present invention is 0.1 wt% to 45 wt% of (S,E)-methyl-7 The present invention relates to a systemic formulation comprising or comprising -(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0274] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0275] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0276] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0277] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 3.5 wt% to 30 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0278] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0279] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable substances. The present invention relates to a systemic formulation comprising or consisting of a salt, 1 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0280] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0281] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0282] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0283] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0284] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0285] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0286] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a phosphate group. The present invention relates to a systemic formulation comprising or including a rimer precipitation inhibitor.

[0287] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0288] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0289] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0290] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0291] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0292] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0293] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydr The present invention relates to a systemic formulation comprising or consisting of lopyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 4.5 wt% to 55 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0294] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0295] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0296] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0297] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0298] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0299] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 0.1 The present invention relates to a systemic formulation comprising or comprising a polymer precipitation inhibitor in an amount ranging from wt% to 40 wt%.

[0300] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0301] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0302] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0303] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0304] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0305] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0306] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0307] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0308] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0309] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0310] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0311] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 0.1 wt% to 40 wt% of a polymer precipitation inhibitor.

[0312] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-di The present invention relates to a systemic formulation comprising or comprising hydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 4.5 wt% to 55 wt% of an acidifying agent, and 2 wt% to 35 wt% of a polymer precipitation inhibitor.

[0313] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 3.5 wt% to 30 wt% of a polymer precipitation inhibitor.

[0314] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, and 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0315] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, and 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0316] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, and 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0317] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% adipic acid, and 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0318] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable substances. The present invention relates to a systemic formulation comprising or consisting of a salt, 3 wt% to 75 wt% adipic acid, and 2 wt% to 35t% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0319] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% adipic acid, and 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0320] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, and 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0321] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, and 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0322] A preferred embodiment of the present invention relates to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% adipic acid, and 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0323] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0324] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose. This relates to a systemic formulation containing or comprising pyrucellulose.

[0325] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0326] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0327] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0328] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0329] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0330] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0331] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0332] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0333] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0334] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0335] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0336] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0337] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydr The present invention relates to a systemic formulation comprising or consisting of lopyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 3 wt% to 75 wt% adipic acid, and 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0338] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0339] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0340] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0341] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0342] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0343] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates. The present invention relates to a systemic formulation comprising, or comprising, a hydrate or pharmaceutically acceptable salt, 3 wt% to 75 wt% adipic acid, and 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0344] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0345] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0346] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0347] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0348] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0349] Embodiments of the present invention relate to systemic formulations comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 15 wt% of a binder. do.

[0350] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0351] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0352] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0353] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0354] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0355] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0356] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0357] Embodiments of the present invention relate to a systemic formulation comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0358] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0359] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0360] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0361] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0362] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydr The present invention relates to a systemic formulation comprising or comprising lopyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0363] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0364] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0365] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0366] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0367] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0368] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, and water. The present invention relates to a systemic formulation comprising or comprising a distillate or pharmaceutically acceptable salt, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0369] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0370] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0371] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0372] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0373] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0374] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder. This relates to a systemic preparation consisting of or .

[0375] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0376] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0377] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0378] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0379] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0380] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0381] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0382] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0383] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0384] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0385] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0386] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 15 wt% povidone K25.

[0387] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino The present invention relates to a systemic formulation comprising or comprising )-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0388] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0389] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0390] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0391] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0392] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0393] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable substances. The present invention relates to a systemic formulation comprising or comprising a salt, 4.5 wt% to 55 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0394] Embodiments of the present invention relate to a systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0395] Embodiments of the present invention relate to systemic formulations comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0396] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0397] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose.

[0398] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0399] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, and water. The present invention relates to a systemic formulation comprising or comprising a dipothetic or pharmaceutically acceptable salt, 3 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0400] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0401] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0402] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0403] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 4.5 wt% to 55 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0404] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0405] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0406] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0407] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0408] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0409] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0410] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, and 3.5 wt The present invention relates to a systemic formulation comprising or comprising % to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0411] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0412] Embodiments of the present invention relate to a systemic formulation comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 4.5 wt% to 55 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0413] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0414] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0415] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0416] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-( The present invention relates to a systemic formulation comprising or comprising 1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% adipic acid, and 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% povidone K25.

[0417] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0418] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0419] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0420] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0421] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, and 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropyl The present invention relates to a systemic formulation comprising or consisting of ropylcellulose and 0 wt% to 12 wt% povidone K25.

[0422] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0423] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 15 wt% binder, 0.1 wt% to 35 wt% disintegrant, and 0.1 wt% to 10 wt% lubricant / flow enhancer.

[0424] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0425] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0426] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0427] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept The present invention relates to a systemic formulation comprising or consisting of -2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0428] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0429] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0430] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0431] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0432] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0433] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, and 1 wt% to 9 wt% lubricant / flow enhancer.

[0434] A preferred embodiment of the present invention is 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, etc. The present invention relates to a systemic formulation comprising or comprising a pharmaceutically acceptable salt, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0435] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or This relates to a systemic formulation comprising or comprising a pharmaceutically acceptable salt, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0436] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or The present invention relates to a systemic formulation comprising or comprising a pharmaceutically acceptable salt, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0437] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0438] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydr The present invention relates to a systemic formulation comprising or comprising lopyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0439] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0440] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0441] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0442] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0443] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer, or This relates to a systemic preparation consisting of [the specified components].

[0444] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0445] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0446] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0447] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0448] A very preferred embodiment of the present invention relates to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0449] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydr The present invention relates to a systemic formulation comprising or comprising lopyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0450] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0451] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0452] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0453] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0454] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer, or This relates to a systemic preparation consisting of [the specified components].

[0455] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, and 0 wt% to 12 wt% of a binder.

[0456] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0457] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0458] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0459] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0460] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates. The present invention relates to a systemic formulation comprising or comprising a hydrate or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0461] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0462] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 15 wt% povidone K25, 0.1 wt% to 35 wt% croscarmellose sodium, and 0.1 wt% to 10 wt% talc or silicon dioxide.

[0463] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0464] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0465] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 1 wt% to 75 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% or The present invention relates to a systemic formulation comprising or consisting of 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0466] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 3 wt% to 75 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0467] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 3 wt% to 75 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0468] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 3 wt% to 75 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0469] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, 0.1 wt% to 40 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0470] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, 2 wt% to 35 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 1 The present invention relates to a systemic formulation comprising or consisting of 2 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0471] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% adipic acid, 3.5 wt% to 30.5 wt% L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% povidone K25, 2 wt% to 35 wt% croscarmellose sodium, and 1 wt% to 9 wt% talc or silicon dioxide.

[0472] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0473] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0474] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0475] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, and 2 wt% to 35 wt% of This invention relates to a systemic formulation comprising or consisting of roscarmellose sodium and 1 wt% to 9 wt% talc or silicon dioxide.

[0476] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0477] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0478] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0479] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0480] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or diacityl phosphate. This relates to a systemic preparation containing or comprising silicon dioxide.

[0481] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0482] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0483] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, 1 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, and 0 wt% to 12 wt% of povidone K25.

[0484] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0485] Embodiments of the present invention relate to a systemic formulation comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0486] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0487] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0488] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0489] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0490] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0491] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 1 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0492] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of adipic acid, and 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0493] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0494] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0495] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0496] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 0.1 wt% to 40 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0497] Embodiments of the present invention relate to a systemic formulation comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, 4.5 wt% to 55 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0498] Embodiments of the present invention relate to systemic formulations comprising, or comprising, 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of adipic acid, 3.5 wt% to 30.5 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

[0499] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 15 wt% binder, 0.1 wt% to 35 wt% disintegrant, 0.1 wt% to 10 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0500] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0501] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino The present invention relates to a systemic formulation comprising or consisting of )-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0502] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0503] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0504] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0505] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0506] Embodiments of the present invention include (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / This relates to a systemic formulation containing or comprising a binder.

[0507] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 0.1 wt% to 40 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0508] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0509] Embodiments of the present invention relate to systemic formulations comprising or comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0510] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts. The present invention relates to a systemic formulation comprising or consisting of wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0511] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts. The present invention relates to a systemic formulation comprising or comprising 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0512] Embodiments of the present invention include 0.1 wt% to 80 wt% (S,E)-methyl-7-(1- The present invention relates to a systemic formulation comprising or comprising (2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% acidifying agent, 3.5 wt% to 30 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0513] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0514] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0515] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0516] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0517] Embodiments of the present invention include 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, and 2 wt% The present invention relates to a systemic formulation comprising or consisting of a polymer precipitation inhibitor from 35 wt%, a binder from 0 wt% to 12 wt%, a disintegrant from 2 wt% to 35 wt%, a lubricant / flow enhancer from 1 wt% to 9 wt%, and a diluent / filler / binder from 0 wt% to 50 wt%.

[0518] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 80 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0519] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0520] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

[0521] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0522] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0523] Embodiments of the present invention include 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1- The present invention relates to a systemic formulation comprising or comprising (2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% acidifying agent, 2 wt% to 35 wt% polymer precipitation inhibitor, 0 wt% to 12 wt% binder, 2 wt% to 35 wt% disintegrant, 1 wt% to 9 wt% lubricant / flow enhancer, and 0 wt% to 50 wt% diluent / filler / binder.

[0524] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 3 wt% to 75 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0525] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0526] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0527] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 4.5 wt% to 55 wt% of an acidifying agent, 3.5 wt% to 30 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0528] Embodiments of the present invention include 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 0.1 wt% to 40 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, and 2 wt% The present invention relates to a systemic formulation comprising or consisting of 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0529] Embodiments of the present invention relate to systemic formulations comprising or comprising 2.5 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, 1 wt% to 9 wt% of a lubricant / flow enhancer, and 0 wt% to 50 wt% of a diluent / filler / binder.

[0530] Embodiments of the present invention relate to systemic formulations comprising or comprising 0.1 wt% to 30.5 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, 1 wt% to 75 wt% o...

Claims

1. Equation (I): 【Chemistry 1】 A systemic formulation comprising (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and at least one polymer precipitation inhibitor.

2. The systemic formulation according to claim 1, wherein the systemic formulation is an oral formulation.

3. The systemic formulation according to claim 1 or claim 2, further comprising at least one acidifying agent and / or at least one binder.

4. The at least one polymer precipitation inhibitor is L-hydroxypropylcellulose, hydroxypropylcellulose, combinations of L-hydroxypropylcellulose and hydroxypropylcellulose, polyethylene alcohol, poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide), polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and sodium carboxymethylcellulose. A systemic preparation according to any one of claims 1 to 3, selected from the group consisting of the following.

5. The systemic formulation according to claim 3 or 4, wherein the at least one acidifying agent is 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, or glutamic acid, and organic tricarboxylic acids such as citric acid or sodium hydrogen citrate.

6. The at least one binder is selected from the group consisting of sugar, sucrose, polysaccharide, xanthan gum, guar gum, carrageenan, starch derived from wheat, corn, rice and potato, pre-aggregated (modified) starch derived from wheat, corn, rice and potato, sodium starch glycolate, natural gum, acacia gum, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, calcium ammonium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, povidone K25, according to any one of claims 3 to 5. formulation.

7. The (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles have a particle size distribution defined by d(0.95) ≤ 25 μm, as described in any one of claims 1 to 6.

8. The systemic preparation according to any one of claims 1 to 7, wherein the systemic preparation is a tablet, a coated tablet, a capsule, a powder, or granules.

9. The systemic formulation according to any one of claims 3 to 8, comprising 1 m / m to 15 m / m of an acidifying agent and 0.1 m / m to 7 m / m of a polymer precipitation inhibitor, wherein the m / m (mass ratio) of the compound is calculated relative to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

10. The systemic formulation according to any one of claims 1 to 9, comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

11. The systemic formulation according to any one of claims 1 to 10, comprising 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

12. A systemic formulation according to any one of claims 1 to 11, for use in the prevention and / or treatment of TG-2 related disease.

13. The aforementioned TG-2-related diseases are preferably, in humans, fibrous liver diseases including nephropathy, NAFLD, NASH, cirrhosis, cholestatic liver diseases such as primary sclerosing cholangitis and primary biliary cholangitis, autoimmune hepatitis, alcoholic steatohepatitis, cystic fibrosis, pulmonary fibrosis, idiopathic pulmonary fibrosis, radiation-induced lung injury, bridging fibrosis, cardiac fibrosis, systemic sclerosis, collagen-induced arthritis, rheumatoid arthritis, atrial fibrosis, A systemic formulation for use according to claim 12, selected from the group consisting of endocardial myocardial fibrosis, old myocardial infarction, angiosclerosis, vascular calcification, fibroproliferative disorders, hypertension, glial scarring, arteriosclerosis, arthral fibrosis, Dupuytren's contracture, keloids, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, IgA nephropathy (IgA-N), progressive nodular fibrosis, retroperitoneal fibrosis, systemic sclerosis, and adhesive capsulitis.

14. The aforementioned TG2-related diseases are a group consisting of nephropathy, NASH, and / or cystic fibrosis. A systemic formulation for use according to claim 12 or claim 13, selected from among the above.

15. The systemic formulation for use according to any one of claims 12 to 14, wherein the TG2-related disease is diabetes-associated fibrosis.

16. Formula (I) for use as a hepatoprotective agent: 【Chemistry 2】 The compound (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts.

17. The compound for use according to claim 16 in protecting the liver from hepatotoxicity, improving liver function, protecting / repairing liver damage, and / or preventing or treating liver disease or liver injury.

18. The compound for use according to claim 16 or claim 17, wherein the compound lowers the serum level of at least one liver enzyme.

19. The compound for use according to claim 18, wherein the at least one liver enzyme is selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

20. The compound for use according to any one of claims 17 to 19, wherein the liver disease or liver disorder is hepatic 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.

21. The compound for use according to any one of claims 17 to 20, wherein the hepatotoxicity, liver injury, liver disease, or liver impairment is caused by at least one hepatotoxic substance, celiac disease, or viral infection.

22. The compound for use according to claim 21, wherein the at least one hepatotoxic substance is selected from the group comprising or comprising toxic chemicals, xenobiotics, anticancer agents, immunosuppressants, analgesics, anti-inflammatory agents, anti-tuberculosis agents, organisms, radiation, heavy metals, mycotoxins, galactosamines, and lipopolysaccharides, celiac disease associated with pathobiology promoted by a specific genophenotype (HLA DQ2 / DQ8) and transglutaminase 2 (TG2), and / or viral infection by hepatitis A, B, or C viruses.

23. The compound for use according to any one of claims 17 to 22, wherein the liver disease or liver impairment is hepatic fibrosis.

24. The compound is administered orally, and is a compound for use according to any one of claims 17 to 23.

25. Formula (I) for use as a hepatoprotective agent: 【Transformation 3】 The compound (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, or its enantiomers, solvates, hydrates, or pharmaceutically acceptable salts, A pharmaceutical composition containing the following:

26. The pharmaceutical composition according to claim 25 for use in protecting the liver from hepatotoxicity, improving liver function, protecting / repairing liver damage, and / or preventing or treating liver disease / liver injury.

27. The compound reduces the serum level of at least one liver enzyme, a pharmaceutical composition for use according to claim 25 or 26.

28. The pharmaceutical composition for use according to claim 27, wherein the at least one liver enzyme is selected from alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP).

29. The pharmaceutically active hepatitis (AIH), alcoholic steatohepatitis (ASH), or liver inflammation described in any one of claims 26 to 28, wherein the liver dysfunction / liver disease is hepatic 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).

30. The pharmaceutical composition for use according to any one of claims 26 to 29, wherein the hepatotoxicity, liver injury, liver disease, or liver impairment is caused by at least one hepatotoxic substance, celiac disease, or viral infection.

31. The aforementioned at least one hepatotoxic substance is a toxic chemical, xenobiotic, anticancer agent, immunosuppressant, analgesic, anti-inflammatory agent, anti-tuberculosis agent, biological, radiation, heavy metal, mycotoxin, galactosamine, and lipopolysaccharide, a specific genophenotype (HLA DQ2 / DQ8) and A compound for use according to claim 30, selected from the group comprising or comprising celiac disease associated with pathobiology promoted by lanceglutaminase 2 (TG2), and / or viral infection by hepatitis A, B, or C viruses.

32. The pharmaceutical composition for use according to any one of claims 25 to 31, further comprising at least one polymer precipitation inhibitor.

33. The pharmaceutical composition for use according to any one of claims 25 to 32, further comprising at least one acidifying agent and / or at least one binder.

34. The pharmaceutical composition for use according to claim 32 or 33, wherein the at least one polymer precipitation 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, and sodium carboxymethylcellulose.

35. The pharmaceutical composition for use according to claim 33 or claim 34, wherein the at least one acidifying agent is 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, or glutamic acid, and organic tricarboxylic acids such as citric acid or sodium hydrogen citrate.

36. The pharmaceutical composition for use according to any one of claims 33 to 35, wherein the at least one binder is selected from the group consisting of sugar, sucrose, polysaccharide, xanthan gum, guar gum, carrageenan, starch derived from wheat, corn, rice and potato, pre-aggregated (modified) starch derived from wheat, corn, rice and potato, sodium starch glycolate, natural gum, acacia gum, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, calcium ammonium alginate, cellulose, cellulose derivatives, hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and povidone K25.

37. (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate particles having a particle size distribution defined by d(0.95) ≤ 25 μm, a pharmaceutical composition for use according to any one of claims 25 to 36.

38. The pharmaceutical composition for use according to any one of claims 25 to 37, wherein the pharmaceutical composition is an oral formulation.

39. The pharmaceutical composition for use according to claim 38, wherein the oral preparation is a tablet, a coated tablet, a capsule, a powder, or granules.

40. The pharmaceutical composition for use according to any one of claims 32 to 39 comprises 1 m / m to 15 m / m of an acidifying agent and 0.1 m / m to 7 m / m of a polymer precipitation inhibitor, wherein the m / m (mass ratio) of the compound is calculated relative to the mass of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate.

41. The pharmaceutical composition for use according to any one of claims 32 to 40 comprises 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 3 wt% to 75 wt% of an acidifying agent, 2 wt% to 35 wt% of a polymer precipitation inhibitor, 0 wt% to 12 wt% of a binder, 2 wt% to 35 wt% of a disintegrant, and 1 wt% to 9 wt% of a lubricant / flow enhancer.

42. The pharmaceutical composition for use according to any one of claims 32 to 41 comprises 0.1 wt% to 45 wt% of (S,E)-methyl-7-(1-(2-(2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydropyridine-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamide)-7-oxohept-2-enoate, 3 wt% to 75 wt% of adipic acid, 2 wt% to 35 wt% of L-hydroxypropylcellulose and / or hydroxypropylcellulose, 0 wt% to 12 wt% of povidone K25, 2 wt% to 35 wt% of croscarmellose sodium, and 1 wt% to 9 wt% of talc or silicon dioxide.

43. The pharmaceutical composition for use according to any one of claims 26 to 42, wherein the liver disease or liver disorder is hepatic fibrosis.

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