Oral formulations of pyridinone derivatives and their use in the prevention and / or treatment of intestinal fibrosis - Patents.com

Abstract

The present invention relates to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, a process for the preparation of said oral formulation, and the medical use of said oral formulation in the prevention or treatment of intestinal fibrosis, in particular fibrostenosing Crohn's disease, said oral formulation comprising or consisting of a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle containing as drug (S,E)-methyl-7-(1-(2-( A plurality of particles comprising 2-ethylbutylamino)-2-oxoethyl)-2-oxo-1,2-dihydro-pyridin-3-ylamino)-6-(1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, comprising a core material, and an enteric coating polymer, wherein each particle is coated with at least one coating layer comprising or consisting of the enteric coating polymer.

Description

Detailed Description of the Invention

[0001] The present invention relates to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, a process for the preparation of said oral formulation, and the medical use of said oral formulation in the prevention or treatment of intestinal fibrosis, in particular fibrostenosing Crohn's disease, said oral formulation comprising a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle containing as drug the (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 an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, comprising a core material, and an enteric coating polymer, wherein each particle is coated with at least one coating layer comprising, or consisting of, a plurality of particles. [Background of the invention]

[0002] Intestinal fibrosis is a common and potentially severe complication in inflammatory bowel disease (IBD) that results from the response of intestinal tissue to the damage caused by chronic inflammation. The traditional view that fibrosis is inevitable or irreversible in IBD patients is gradually changing in light of advances in the understanding of the cellular and molecular mechanisms underlying the pathogenesis of fibrosis in general, and intestinal fibrosis in particular.

[0003] Intestinal fibrosis is a common but debilitating complication of Crohn's disease, and there is currently no cure for intestinal fibrosis. Crohn's disease (CD) is a type of inflammatory bowel disease that results in sites of chronic inflammation anywhere in the gastrointestinal tract. Crohn's disease primarily affects the small and large intestines.

[0004] In many cases, significant fibrosis is already present at the time of disease diagnosis, and 40%-70% of Crohn's disease patients require surgery within 10 years of diagnosis, with the development of fibrotic structures being the indication for surgery in small bowel disease. Fibrosis occurs due to excessive deposition of extracellular matrix (ECM), especially fibrillar collagen, and dysregulation of ECM turnover.

[0005] Transglutaminase 2 (TG2) is known to be activated in the inflamed intestine in IBD patients, and significant high levels of TG2 autoantibodies have been detected in serum of Crohn's disease. (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) is an effective inhibitor of transglutaminase 2.

[0006] However, designing pharmaceutical formulations suitable for gastrointestinal drug delivery, especially for selective localized drug release to the small intestine, via the oral route, for treating intestinal fibrosis, particularly fibrostenosing Crohn's disease, remains a problem.

[0007] It is an object of the present invention to provide an oral 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-carboxamido)-7-oxohept-2-enoate of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, as a drug suitable for selective delivery to the small intestine of a mammal for the prevention or treatment of intestinal fibrosis, in particular fibrostenosing Crohn's disease.

[0008] The object of the present invention is solved by the teaching of the independent claims. Further advantageous features, aspects and details of the invention are evident from the dependent claims, the description, the drawings and the examples of the present application. [Brief Description of the Invention]

[0009] The object of the present invention is solved by an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle containing as drug (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 of formula (I)

[0010] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, and an enteric coating polymer, wherein each particle is coated with at least one coating layer comprising or consisting of the enteric coating polymer.

[0011] As used herein, the compound of formula (I) is also referred to as Compound 1 or Comp. 1.

[0012] Preferably, in the oral formulation of the present invention, the enteric coating polymer has an average molecular weight >100,000 g / mol and is selected from methacrylic acid-methacrylic acid ester copolymer, acrylic acid-methacrylic acid ester copolymer, methacrylic acid-acrylic acid ester copolymer, acrylic acid ester-methacrylic acid ester-methacrylic acid copolymer, where the ester is a methyl ester, ethyl ester, propyl ester, iso-propyl ester, or butyl ester, preferably a methyl ester or an ethyl ester, and most preferably a methyl ester.

[0013] More preferably, the enteric coating polymer is selected from methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the aforementioned enteric coating polymers.

[0014] Even more preferably, the enteric coating polymer comprises or is selected from the group consisting of: hypromellose acetate succinate (HPMCAS), hypromellose phthalate, methacrylic acid-methyl methacrylate copolymers such as Eudragit® L100, Eudragit® L12.5, Eudragit® L12.5P, Eudragit® L30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® L200-250, Eudragit® L100-250, Eudragit® L2 ... Enteric coating polymers include, but are not limited to, Eudragit® S12.5, Eudragit® S12.5P, Eudragit® RS100, Eudragit® RL100, Eudragit® RL12.5, Eudragit® RS12.5, Eudragit® FS30D, methacrylic acid-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers. More preferably, the hypromellose acetate succinate is selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0015] The core material is preferably in the form of a core pellet and is preferably selected from the group comprising or consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, and preferably microcrystalline cellulose.

[0016] Furthermore, the present invention refers to the oral formulation described above, wherein each particle is coated with an additional coating layer that includes or consists of a sustained release polymer in addition to the enteric coating that includes or consists of an enteric coating polymer. This sustained release layer includes or consists of a sustained release polymer preferably selected from hypromellose (HPMC), ethylcellulose, ammonio methacrylate copolymers such as Eudragit® RL100 and Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5, etc., and mixtures thereof. When the sustained release polymer is ethylcellulose, it optionally further comprises polyethylene glycol (PEG) as a plasticizer, preferably Macrogol® 6000.

[0017] The oral formulations of the present invention have been found to release (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, its enantiomer, solvate, hydrate, or pharma- ceutically acceptable salt beginning in the jejunum and completing the release in the ileum.

[0018] Furthermore, the oral formulations of the present invention are useful for the prevention and / or treatment of intestinal fibrosis, particularly fibrostenosing Crohn's disease.

[0019] The oral formulation of the present invention is prepared by a method comprising: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, Including, Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer. Optionally, the invention further comprises: Step C) Coating each particle with a coating solution containing a sustained release polymer. [Description of the Invention]

[0020] The present invention relates to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle is composed 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 of formula (I):

[0021] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, a core material, and an enteric coating polymer, wherein each particle is coated with at least one coating layer comprising or consisting of the enteric coating polymer.

[0022] The term "oral formulation" as used herein refers to a formulation that is a drug that is administered through the mouth. As used herein, "selective delivery of a drug to the small intestine" means that the formulation is gastroresistant and can withstand gastric fluids and release the active ingredient in the intestine.

[0023] As used herein, the term "mammal" refers to an animal or a human, preferably a patient suffering from intestinal fibrosis, in particular fibrostenosing Crohn's disease.

[0024] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a specified component which has the same activity as the unmodified compound and which is not biologically or otherwise undesirable. 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 hydrogen citrate, alginic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, bisulfic acid, boric acid, butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid, citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulfuric acid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid, glycerol, and the like. Acids include phosphoric, glycine, glucoheptanoic, gluconic, glutamic, glutaric, glycolic, hemisulfonic, heptanoic, hexanoic, hippuric, hydrobromic, hydrochloric, hydroiodic, hydroxyethanesulfonic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, naphthylanesulfonic, naphthylic, nicotinic, nitrous, oxalic, pelargonic, phosphoric, propionic, saccharinic, salicylic, sorbic, succinic, sulfuric, tartaric, thiocyanic, thioglycolic, thiosulfuric, tosylic, undecylenic, and amino acids of natural and synthetic origin.

[0025] The term "solvate" as used herein refers to a form in which a compound, in particular (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, forms a complex through coordination with a solvent molecule.

[0026] The term "hydrate" as used herein refers to a form in which a compound, in particular (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, forms a complex through coordination with a water molecule.

[0027] As used herein, the term "effective amount" or "therapeutically effective amount" of an active agent or pharmaceutical active agent or drug or pharmaceutical active ingredient is used interchangeably herein and refers to the amount of active agent or pharmaceutical active ingredient or drug or pharmaceutical active ingredient sufficient to produce a positive effect. Thus, these amounts are sufficient to treat the disease of interest, yet low enough to avoid serious side effects. A therapeutically effective amount of a pharmaceutical active agent, when applied repeatedly over time, will cause substantial relief of symptoms. The effective amount of a pharmaceutical active agent will vary depending on the particular condition or conditions being treated, the severity of the condition, the duration of treatment, the particular components of the composition being used, and similar factors.

[0028] As used herein, the terms "active agent", "pharmaceutical active agent", "drug" or "active pharmaceutical ingredient" are used interchangeably herein and refer to a compound that exhibits a therapeutic effect in mammals, particularly humans.

[0029] The term "enteric coating polymer" as used herein refers to a polymer applied to oral medications that prevents the dissolution or disintegration in the stomach environment and helps release the drug after the stomach, usually in the intestine, preferably in the small intestine, by protecting the drug from the acidity of the stomach and the stomach from the harmful effects of the drug, respectively. Granules, pellets, beads, minicapsules and minitablets are the preferred enteric polymer coated dosage forms in the present invention.

[0030] Preferably, the oral formulation of the present invention comprises an enteric coating polymer in the range of 1 wt% to 40 wt%, preferably 1 wt% to 35 wt%, more preferably 1 wt% to 30 wt%, most preferably 1 wt% to 26 wt%.

[0031] The highly acidic gastric environment (pH 1.5-2 in fasting state) rapidly increases to pH 6 in the duodenum and along the small intestine to pH 7.4 at the terminal ileum. Thus, oral formulations should be retained in the acidic gastric environment and be able to dissolve in the small intestine.

[0032] Thus, the oral formulation of the present invention comprises an enteric coating polymer, and the enteric coating polymer is soluble at pH values ​​ranging from 5.0 to 7.5, preferably from 5.0 to 7.0, more preferably from 5.5 to 7.0, and most preferably from 5.5 to 6.8.

[0033] Preferably, the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers.

[0034] Thus, in some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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 of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, an enteric coating polymer, and wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer; and The enteric coating polymer comprises or is selected from the group consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers.

[0035] Hypromellose is also known as hydroxypropyl methylcellulose (HPMC), and thus hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate, or HPMCAS) is the acetate / succinate ester of hydroxypropyl methylcellulose. Hypromellose phthalate (hydroxypropyl methylcellulose phthalate, or HPMCP) is the phthalate ester of hydroxypropyl methylcellulose. Hypromellose (HPMC), hypromellose acetate succinate (HPMCAS), and hypromellose phthalate (HPMCP) each have the following chemical structure:

[0036] [ka]

[0037] HPMCAS is a cellulosic polymer with four types of semi-randomly substituted substituents at the hydroxyl: methoxy with a mass content of 12 wt%-28 wt%, hydroxypropyl with a mass content of 4 wt%-23 wt%, acetate with a mass content of 2 wt%-16 wt%, and succinate with a mass content of 4 wt%-28 wt%. The succinate groups of HPMCAS have a pKa of about 5, such that the polymer is less than 10% ionized at pH values ​​below about 4, and at least 50% ionized at pH values ​​of about 5 or greater. Due to the presence of the relatively hydrophobic methoxy and acetate substituents, HPMCAS is water insoluble when unionized (about pH<5) and remains primarily colloidal at intestinal pH (i.e., pH 6.0-7.5).

[0038] There are nine grades of HPMCAS with different particle sizes (fine, medium, granular) and chemical substitution levels of acetyl and succinoyl groups to achieve an initial pH range of 5.5-6.5 (Shin-Etsu AQOAT® enteric coating, or Ashland AquaSolve™).

[0039] [Table 1]

[0040] In some preferred embodiments, the oral formulations described herein are characterized in that the enteric coating polymer is hypromellose acetate succinate (HPMCAS), and said HPMCAS is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, and more preferably HPMCAS-HF. Thus, the present invention refers to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle comprising: a plurality of particles 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-carboxamido)-7-oxohept-2-enoate of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, and an enteric coating polymer; and wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer; and The enteric coating polymer is hypromellose acetate succinate (HPMCAS), and said HPMCAS is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, and more preferably HPMCAS-HF.

[0041] Cellulose acetate phthalate (CAP), also known as cellulose acetate (INN), is a cellulose polymer in which approximately half of the hydroxyls are esterified with acetyl, one quarter are esterified with one or two carboxyls of phthalic acid, and the remainder is unchanged. CAP has the following chemical structure:

[0042] [ka]

[0043] As used herein, the term "(meth)acrylic acid-(meth)acrylate copolymer" refers to a copolymer of acrylic acid or an acrylic acid ester with methacrylic acid or a methacrylic acid ester having a molecular mass (abbreviated Mr), formerly also called molecular weight, of Mr > 100,000 and having the following general formula:

[0044] [ka]

[0045] During the ceremony, R 1 is most preferably -H or -CH3, and R 2 and R 3 are, independently of each other, -H or an ester group, preferably a methyl, ethyl, propyl, isopropyl, or butyl ester.

[0046] Preferred are Eudragit® copolymers, such as Eudragit® L100, Eudragit® L12.5, Eudragit® L12.5P, Eudragit® L30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® S12.5, Eudragit® S12.5P, Eudragit® RS100, Eudragit® RL100, Eudragit® RL12.5, Eudragit® RS12.5, Eudragit® FS30D, and mixtures of two or three of these Eudragit® copolymers, and more preferably Eudragit® L100, Eudragit® S100, and mixtures thereof. Eudragit® S100, Eudragit® S12.5, Eudragit® S12.5P (Evonik) have a methacrylic acid:methyl methacrylate ratio of 1:2 and an average relative molecular weight of about 135,000. The ratio of carboxylic acid groups to ester groups is about 1:2. In the Eudragit® S copolymer, the residue R 2 and R 3 is -H, which means that 25% to 35% of the carbonyloxy moieties are carboxyl groups (-COOH). The content of carboxyl groups in Eudragit® S copolymer is preferably 30%±1%.

[0047] Eudragit® L100, Eudragit® L12.5, Eudragit® L12.5P (Evonik) have a methacrylic acid:methyl methacrylate ratio of 1:1 and an average relative molecular weight of about 250000. The ratio of carboxylic acid groups to ester groups is about 1:1.

[0048] Eudragit® L100-55 and Eudragit® L30D-55 (Evonik) have a 1:1 ratio of methacrylic acid:ethyl acrylate and an average relative molecular weight of about 250000. The ratio of carboxyl groups to ester groups is about 1:1.

[0049] In the Eudragit® L copolymer, the residue R 2 and R 3 is -H, which means that 45% to 55% of the carbonyloxy moieties are carboxyl groups (-COOH). The content of carboxyl groups in Eudragit® L copolymer is preferably 50%±1%.

[0050] Eudragit® FS30D (Evonik) has a ratio of methyl acrylate, methyl methacrylate, and methacrylic acid of 7:3:1 and an average molecular weight of 280,000 g / mol. The ratio of free carboxyl groups to ester groups is about 1:10.

[0051] These polymers are gastro-resistant and enteric polymers. Their polymer films are insoluble in pure water and dilute acid. Their polymer films dissolve at higher pH depending on the carboxylic acid content. Eudragit® S copolymers and Eudragit® L copolymers can be used as single components in the polymer coating or in combination in any ratio. By using a combination of polymers, the polymer material can exhibit solubility at a pH between the pH at which Eudragit® L copolymers and Eudragit® S copolymers are separately soluble.

[0052] In an embodiment of the oral formulation described herein, the enteric coating polymer is selected from the group consisting of methacrylic acid-methacrylic acid ester copolymer, acrylic acid-methacrylic acid ester copolymer, methacrylic acid-acrylic acid ester copolymer, acrylic acid-acrylic acid ester copolymer, and more preferably methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, and even more preferably Eudragit® L100, Eudragit® L200, ... Eudragit® L12.5, Eudragit® L12.5P, Eudragit® L30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® S12.5, Eudragit® S12.5P, Eudragit® FS30D, and mixtures of two or three of these Eudragit® copolymers, and most preferably Eudragit® L100, Eudragit® S100, or mixtures thereof.

[0053] Eudragit (registered trademark) L100-x:y=1:1 (ratio of methacrylic acid:methyl methacrylate units), Eudragit (registered trademark) S100-x:y=1:2 (ratio of methacrylic acid:methyl methacrylate units), n = degree of polymerization.

[0054] [ka]

[0055] Preferably, the present invention refers to an oral formulation adapted for selective delivery of a drug (i.e., Compound 1) to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate as a drug, or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer; and the enteric coating polymer is selected from hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, or a mixture of one or more of these enteric coating polymers; or having an average molecular weight >100,000 g / mol, preferably an average molecular weight between 120,000 g / mol and 270,000 g / mol, and represented by the general formula:

[0056] [ka]

[0057] During the ceremony, R 1 is -H or -CH3, and R 2 is -H, and R 3 is selected from methyl, ethyl, propyl, iso-propyl, butyl, or dimethylaminoethyl; or R 3 is -H, and R 2 is selected from methyl, ethyl, propyl, iso-propyl, or butyl; More preferably, the enteric coating polymer is a methacrylic acid-methacrylic acid ester copolymer, an acrylic acid-methacrylic acid ester copolymer, a methacrylic acid-acrylic acid ester copolymer, an acrylic acid ester-methacrylic acid ester-methacrylic acid copolymer, wherein the ester is a methyl ester, an ethyl ester, a propyl ester, an iso-propyl ester, or a butyl ester, more preferably a methyl ester, or an ethyl ester, or a mixture thereof, and most preferably a methyl ester; Thus, even more preferably, the enteric coating polymer is selected from hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, or a mixture of one or more of these enteric coating polymers, Even more preferably, the enteric coating polymer has an average molecular weight >100,000 g / mol, preferably an average molecular weight of 120,000 g / mol to 270,000 g / mol, and is represented by one of the following two general formulas:

[0058] [ka]

[0059] During the ceremony, n = Degree of polymerization and the ratio of x:y is in the range of 1:0.5 to 1:2.5, preferably 1:0.8 to 1:2.2; or

[0060] [ka]

[0061] During the ceremony n = Degree of polymerization and the ratio of x:y is in the range of 1:0.5 to 1:2.5, preferably 1:0.8 to 1:2.2; Even more preferably, the enteric coating polymer is selected from the group comprising or consisting of: Eudragit® L100, Eudragit® L12.5, Eudragit® L12.5P, Eudragit® L30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® S12.5, Eudragit® S12.5P, Eudragit® FS30D, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or three of these Eudragit® copolymers.

[0062] The methacrylate copolymers can be combined in any desired ratio, and the ratio can be modified to modify the drug release rate. The ratio of Eudragit® L100:Eudragit® S100 can range from 100:0 to 50:50, preferably 100:0 to 60:40, 100:0 to 70:30, more preferably 100:0 to 80:20, or any ratio therebetween, and most preferably the ratio of Eudragit® L100:Eudragit® S100 is 100:0 to 85:15.

[0063] In all embodiments disclosed herein, the core material is preferably in the form of core pellets or granules, and is preferably selected from the group comprising or consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, and is preferably microcrystalline cellulose.

[0064] The term "core material in the form of core pellets" as used herein means preparing core pellets consisting of only core material or a mixture of the aforementioned core materials. These core pellets do not contain drug (i.e., Compound 1) and do not contain enteric coating polymer or sustained release polymer. These core pellets are coated with a drug-containing layer, an enteric coating layer, and optionally a sustained release layer. Instead of the term "layer", the term "coating" can be used as an alternative. If present, the sustained release layer can also be above the enteric coating layer or below the enteric coating layer.

[0065] The term "core material in the form of granules" used herein means that the core material or the mixture of the aforementioned core materials as the main component is mixed with drug and optionally with further components to obtain a composition to form granules.These granules contain Compound 1, possibly in a uniformly distributed manner, and are coated with an enteric coating layer and optionally with a sustained release layer.If present, the sustained release layer can be on top of the enteric coating layer or under the enteric coating layer.

[0066] As a result, the present invention refers to an oral formulation adapted for the selective delivery of a drug (i.e., Compound 1) to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate as a drug, or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, and a plurality of particles comprising an enteric coating polymer; wherein each core material is selected from tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, and is preferably microcrystalline cellulose; and wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer; and the enteric coating polymer is selected from hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, or a mixture of one or more of these enteric coating polymers; or having an average molecular weight >100,000 g / mol, preferably an average molecular weight between 120,000 g / mol and 270,000 g / mol, and represented by the general formula:

[0067] [ka]

[0068] During the ceremony, R 1 is -H or -CH3, and R 2 is -H, and R 3 is selected from methyl, ethyl, propyl, iso-propyl, butyl, or dimethylaminoethyl; or R 3 is -H, and R 2 is selected from methyl, ethyl, propyl, iso-propyl, or butyl; More preferably, the enteric coating polymer is a methacrylic acid-methacrylic acid ester copolymer, an acrylic acid-methacrylic acid ester copolymer, a methacrylic acid-acrylic acid ester copolymer, an acrylic acid ester-methacrylic acid ester-methacrylic acid copolymer, wherein the ester is a methyl ester, an ethyl ester, a propyl ester, an iso-propyl ester, or a butyl ester, more preferably a methyl ester, or an ethyl ester, or a mixture thereof, and most preferably a methyl ester; Thus, even more preferably, the enteric coating polymer is selected from hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, or a mixture of one or more of these enteric coating polymers, Even more preferably, the enteric coating polymer has an average molecular weight >100,000 g / mol, preferably an average molecular weight of 120,000 g / mol to 270,000 g / mol, and is represented by one of the following two general formulas:

[0069] [ka]

[0070] During the ceremony, n = Degree of polymerization and the ratio of x:y is in the range of 1:0.5 to 1:2.5, preferably 1:0.8 to 1:2.2; or

[0071] [ka]

[0072] During the ceremony n = Degree of polymerization and the ratio of x:y is in the range of 1:0.5 to 1:2.5, preferably 1:0.8 to 1:2.2; Even more preferably, the enteric coating polymer is selected from the group comprising or consisting of: Eudragit® L100, Eudragit® L12.5, Eudragit® L12.5P, Eudragit® L30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® S12.5, Eudragit® S12.5P, Eudragit® FS30D, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or three of these Eudragit® copolymers.

[0073] Thus, more preferably, the present invention refers to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), Core material, and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer; and The enteric coating polymer is a methacrylic acid-methyl methacrylate copolymer, and the methacrylic acid-methyl methacrylate copolymer is Eudragit® L100, Eudragit® S100, or a mixture thereof. The mixture of Eudragit® L100 and Eudragit® S100 may have a ratio ranging from 100:0 to 50:50, preferably 95:5 to 60:40, 90:10 to 70:30, more preferably 90:10 to 80:20, or any ratio in between, and most preferably the ratio of Eudragit L100:Eudragit S100 is 85:15.

[0074] After administration of the oral formulation of the present invention, the administered drug dose must dissolve quickly and completely.The pH change in the stomach after oral administration must be adjusted to ensure that the administered drug dose is dissolved.The greater the systemic availability (AUC) in combination with the mucosal release in the small intestine, the greater the expected pharmacological effect.

[0075] In some embodiments, in the oral formulations described above, each particle further comprises one or more binders, buffers, colorants, flow agents, plasticizers, disintegrants, pH-adjusting agents, surfactants, and / or bulking agents.

[0076] In all embodiments disclosed herein, the enteric coating layer comprises or consists of an enteric coating polymer. Additionally, the enteric coating polymer is preferably included in or forms the outer layer of the oral formulations disclosed herein.

[0077] Additionally, Compound 1 is preferably included in the core material without an additional drug (ie, Compound 1) layer, or is not included in the core material but only in a drug layer that coats the core material. The enteric coating layer covers the core material or drug layer. However, an additional sustained release layer may be present as an outermost layer on the enteric coating layer, or beneath the enteric coating layer but above the drug layer or drug-containing core, to fine-tune the release of Compound 1.

[0078] In some embodiments, in the oral formulations described above, the enteric coating polymer is included in or forms the outer layer of the coating that surrounds the core material.

[0079] Thus, the present invention refers to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle comprising: A plurality of particles 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-carboxamido)-7-oxohept-2-enoate of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, an enteric coating polymer, and the core material comprises one or more binders, buffers, colorants, plasticizers, flow agents, disintegrants, pH-adjusting agents, surfactants and / or fillers; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0080] Preferably, the oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle comprising: A plurality of particles 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 of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, an enteric coating polymer, and the core material comprises one or more binders, buffers, colorants, plasticizers, flow agents, disintegrants, pH-adjusting agents, surfactants and / or fillers; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of said enteric coating polymers.

[0081] More preferably, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), a core material comprising one or more binders, buffers, colorants, plasticizers, flow agents, disintegrants, pH-adjusting agents, surfactants and / or fillers; a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the enteric coating polymer is a hypromellose acetate succinate selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or The methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0082] In some embodiments, the present invention is directed to oral formulations in which the enteric coating polymer is included in or forms the outer layer of the coating that surrounds the core material. Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle comprising A plurality of particles 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-carboxamido)-7-oxohept-2-enoate of formula (I), or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), a core material, and an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the enteric coating polymer is included in or forms the outer layer of the coating surrounding the core material.

[0083] In addition to granules / pellets / beads, multiparticulate formulations also include mini-tablets with a typical diameter of 1-4 millimeters. Mini-tablets are obtained by a different manufacturing operation than spherical particles, but offer the same advantages. Mini-tablets are particularly preferred for pediatric applications.

[0084] In some embodiments, the present invention is directed to oral formulations, where the particles are in the form of coated mini-tablets, and the core material comprises one or more binders, disintegrants, flow agents, pH-adjusting agents, and / or fillers. Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated mini-tablets, each particle being (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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), a core material comprising one or more binders, buffers, disintegrants, flow agents, pH-adjusting agents, and / or fillers; a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, preferably the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of said enteric coating polymers, more preferably Preferably, the enteric coating polymer is hypromellose acetate succinate, and said hypromellose acetate succinate is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0085] Preferably, the binder is selected from the group consisting of sugars, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches from wheat, corn, rice and potato, pre-agglomerated (modified) starches from wheat, corn, rice and potato, sodium starch glycolate, natural gums, acacia gum, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropyl cellulose, L-hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidones such as povidone K25, and mixtures thereof.

[0086] More preferably, the binder is hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, or polyvinylpyrrolidone such as Povidone K25. Most preferably, the binder is low-substituted hydroxypropylcellulose or Povidone K25. Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated mini-tablets, each particle being (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 an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt thereof; The core material, which comprises one or more binders, buffers, disintegrants, flow agents, pH-adjusting agents, and / or fillers, and the binder is hydroxypropylcellulose, L-hydroxypropylcellulose, low-substituted hydroxypropylcellulose, or a polyvinylpyrrolidone such as Povidone K25. Most preferably, the binder is low-substituted hydroxypropylcellulose or Povidone K25; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0087] Hydroxypropyl cellulose is a partially substituted poly(hydroxypropyl) ether of cellulose. Hydroxypropyl cellulose may contain up to 0.6% silica or other suitable anti-caking agents. Hydroxypropyl cellulose is commercially available in many different grades with various solution viscosities. The 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 on the dry substrate. The average degree of polymerization ranges from 200 to 300. The molar degree of substitution is about 4.

[0088] "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 a variety of grades with different particle sizes and substitution levels. Low-substituted hydroxypropyl cellulose contains 5% to 16% hydroxypropoxy groups on dry substrate. The molar degree of substitution is <1. In particular, low-substituted hydroxypropyl cellulose is a low-substituted O-(2-hydroxypropylated) cellulose containing 5wt% to 16wt%, preferably 7wt% to 13wt% hydroxyproxy groups (-OCH2CHOHCH3), calculated on dry substrate. Low-substituted hydroxypropyl cellulose has an average particle size ranging from 15μm to 65μm, preferably from 25μm to 60μm, more preferably from 25μm to 60μm.

[0089] "Povidone" is used synonymously with polyvinylpyrrolidone (PVP). Polyvinylpyrrolidone consists of a linear polymer of 1-ethenylpyrrolidin-2-one. The various types of polyvinylpyrrolidone are characterized by the viscosity of the solution, represented by the K value. Polyvinylpyrrolidone exists as a white to off-white powder or flake, and dissolves easily 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), between 28,000 g / mol (Da) and 34,000 g / mol (Da).

[0090] Preferably, the pH adjuster is selected from the group consisting of ascorbic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, tartaric acid, fumaric acid, maleic acid, malic acid, adipic acid, glutamic acid, citric acid, and sodium hydrogen citrate, more preferably adipic acid.

[0091] Thus, a preferred embodiment of the present invention is directed to oral formulations, in which when the particles are in the form of coated minitablets, the core material comprises one or more binders, disintegrants, flow agents, pH-adjusting agents and / or fillers, in which The binder is low-substituted hydroxypropyl cellulose or hydroxypropyl cellulose; The disintegrant is croscarmellose sodium. The superplasticizer is talc, The pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol.

[0092] Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) a core material comprising one or more binders, disintegrants, flow agents, pH-adjusting agents, surfactants and / or fillers; wherein the binder is low-substituted hydroxypropyl cellulose or hydroxypropyl cellulose; The disintegrant is croscarmellose sodium. the flow agent is talc, the pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol, and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer. Preferably, the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP). , shellac, and mixtures of two or more of said enteric coating polymers, preferably the enteric coating polymer is selected from the group comprising or consisting of: hypromellose acetate succinate (HPMCAS), hypromellose phthalate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of said enteric coating polymers.

[0093] More preferably, the enteric coating polymer is hypromellose acetate succinate, and said hypromellose acetate succinate is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0094] In some embodiments, the present invention refers to an oral formulation, wherein at least one coating layer further comprises at least one buffering agent, plasticizer, and / or flow agent.

[0095] Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated mini-tablets, each particle 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-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt thereof; a plurality of particles comprising a core material and an enteric coating polymer; the core material comprises or consists of at least one buffer, plasticizer, and / or flow agent; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0096] Preferably, the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the aforementioned enteric coating polymers, and More preferably, the enteric coating polymer is selected from the group comprising or consisting of: hypromellose acetate succinate (HPMCAS), hypromellose phthalate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers.

[0097] The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0098] Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), a core material comprising one or more binders, disintegrants, flow agents, and / or fillers; wherein the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a mixture thereof; The disintegrant is croscarmellose sodium. The flow agent is talc, silicon dioxide, or a mixture thereof; The pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, at least one buffering agent, plasticizer, and / or flow agent, preferably the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of said enteric coating polymers.

[0099] The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0100] Preferably, the buffering agent is ammonium bicarbonate, the plasticizer is triethyl citrate, and / or the flow agent is talc. Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt thereof; a core material comprising one or more binders, disintegrants, flow agents, and / or fillers; wherein the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a mixture thereof; The disintegrant is croscarmellose sodium. The flow agent is talc, silicon dioxide, or a mixture thereof; The pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, at least one buffering agent, plasticizer, and / or flow agent, preferably the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of said enteric coating polymers.

[0101] The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0102] Thus, said oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), a core material comprising one or more binders, disintegrants, flow agents, pH-adjusting agents, and / or fillers; wherein the binder is low-substituted hydroxypropyl cellulose, or hydroxypropyl cellulose; The disintegrant is croscarmellose sodium. The flow agent is talc, silicon dioxide, or a mixture thereof; The pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, at least one buffering agent, a plasticizer, and / or a flow agent; The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The flow agent is talc, silicon dioxide, or a mixture thereof; Preferably, the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers.

[0103] The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0104] Preferably, the present invention is directed to an oral formulation as previously described, where each particle contains 5 wt% to 15 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, an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt thereof, and 50wt% to 90wt% core material comprising or consisting of a binder, a disintegrant, a flow agent, a pH adjuster and / or a filler, and 1wt%-10wt% of enteric coating polymer.

[0105] In some embodiments, the present invention is directed to an oral formulation as described above, wherein each particle in the form of a coated ministate comprises: 5 wt% to 15 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, an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt thereof, and 50 wt. % to 90 wt. % of a core material comprising or consisting of a binder, a disintegrant, a flow agent, a pH adjuster and / or a filler, and 1wt%-10wt% of enteric coating polymer.

[0106] In some preferred embodiments, the present invention is directed to an oral formulation as described above, wherein each particle comprises or consists of: 5 wt% to 15 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, HPMCAS from 1wt% to 10wt%, 15 wt% to 30 wt% low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 15 wt% to 30 wt% croscarmellose sodium, 15wt% to 30wt% mannitol, 0.1 wt% to 3.0 wt% triethyl citrate; 0 wt% to 1.0 wt% ammonium bicarbonate, and 5 wt % to 10 wt % of talc, silicon dioxide, or a mixture thereof; Optionally 5.0 wt% to 10.0 wt% adipic acid.

[0107] Preferably, the present invention is directed to an oral formulation as previously described, wherein each particle in the form of a coated mini-tablet comprises or consists of: 5 wt% to 15 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, Core materials including: 15 wt% to 30 wt% low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 15 wt% to 30 wt% croscarmellose sodium, 15 wt% to 30 wt% mannitol, and optionally 5.0 wt% to 10.0 wt% adipic acid, At least one coating layer comprising: 1wt% to 10wt% HPMCAS, 0 wt% to 1.0 wt% ammonium bicarbonate, 0.1 wt% to 3.0 wt% triethyl citrate, and 5wt% to 10wt% of talc, silicon dioxide, or mixtures thereof.

[0108] In some preferred embodiments, the present invention is directed to an oral formulation as described above, wherein each particle comprises or consists of: 5 wt% to 15 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, 1 wt% to 10 wt% Eudragit® L100 / S100, preferably 1 wt% to 10% Eudragit® L100 and 0 wt% to 5 wt% Eudragit® S100, 15 wt% to 30 wt% low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 15 wt% to 30 wt% croscarmellose sodium, 15wt% to 30wt% mannitol, 0.1 wt% to 3.0 wt% triethyl citrate; 3 wt % to 10 wt % of talc, silicon dioxide, or a mixture thereof, and Optionally 5.0 wt% to 10.0 wt% adipic acid.

[0109] Preferably, the present invention is directed to an oral formulation as previously described, wherein each particle in the form of a coated mini-tablet comprises or consists of: 5 wt% to 15 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, Core materials including: 20 wt% to 30 wt% low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 20wt% to 30wt% croscarmellose sodium, 20wt% to 30wt% mannitol, optionally 5.0 wt% to 10.0 wt% adipic acid, At least one coating layer comprising: 15wt% to 25wt% Eudragit® L100 / S100, preferably 1wt% to 10wt% Eudragit® L100 and 0wt% to 5wt% Eudragit® S100, 0.1 wt% to 3.0 wt% triethyl citrate, and / or 3wt% to 10wt% of talc, silicon dioxide, or mixtures thereof.

[0110] More preferably, the present invention is directed to an oral formulation as described above, wherein each particle is in the form of a coated mini-tablet, and each particle consists of: 8 wt% to 12 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, 3 wt% to 8 wt% HPMCAS, or 3 wt% to 8 wt% Eudragit® L100 / S100; 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, 0.1 wt% to 1.0 wt% triethyl citrate, 0.01wt% to 1.0wt% ammonium bicarbonate, 4 wt% to 8 wt% talc, and 0.5 wt% to 1.5 wt% silicon dioxide, and Optionally, 5 wt% to 10.0 wt% adipic acid.

[0111] More preferably, it is an oral formulation as described above, wherein each particle is in the form of a coated mini-tablet, and Each particle consists of: 8 wt% to 12 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, Core materials including: 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, Optionally, 5 wt. % to 10.0 wt. % adipic acid, At least one coating layer comprising: 3 wt% to 8 wt% HPMCAS, or 3 wt% to 8 wt% Eudragit® L100 / S100; 0.1 wt% to 1.0 wt% triethyl citrate, 0.01wt% to 1.0wt% ammonium bicarbonate, 4 wt% to 8 wt% talc, and 0.5wt% to 1.5wt% silicon dioxide.

[0112] Even more preferably, the present invention is directed to an oral formulation as previously described, wherein each particle is in the form of a coated mini-tablet, and Each particle consists of: 8 wt% to 12 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, 3wt% to 6wt% HPMCAS, 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, 0.1 wt% to 1.0 wt% triethyl citrate, 0.01wt% to 0.5wt% ammonium bicarbonate, 4 wt% to 8 wt% talc, and 0.5 wt% to 1.5 wt% silicon dioxide, and Optionally, 6 wt. % to 10.0 wt. % adipic acid, or Each particle consists of: 8 wt% to 12 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, 3 wt% to 6 wt% Eudragit® L100, 0.1 wt% to 1.5 wt% Eudragit® S100, 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, 0.1 wt% to 1.0 wt% triethyl citrate, 4wt% to 8wt% talc, 0.5 wt% to 1.5 wt% silicon dioxide, and Optionally, 6 wt% to 10.0 wt% adipic acid.

[0113] Even more preferably, the present invention is directed to an oral formulation as described above, wherein each particle is in the form of a coated mini-tablet, and Each particle consists of: 8 wt% to 12 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, Core materials including: 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, Optionally, 6 wt% to 10 wt% adipic acid, and At least one coating layer comprising: 3wt% to 6wt% HPMCAS, 0.1 wt% to 1.0 wt% triethyl citrate, 0.01wt% to 0.5wt% ammonium bicarbonate, 4 wt% to 8 wt% talc, and 0.5 wt% to 1.5 wt% silicon dioxide; or Each particle consists of: 8 wt% to 12 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, Core materials including: 20 wt% to 26 wt% low-substituted hydroxypropyl cellulose; 2 wt% to 4 wt% hydroxypropylcellulose; 20wt% to 26wt% croscarmellose sodium, 20wt% to 26wt% mannitol, Optionally, 6 wt% to 10 wt% adipic acid, and At least one coating layer comprising: 3 wt% to 6 wt% Eudragit® L100, 0.1 wt% to 1.5 wt% Eudragit® S100, 0.1 wt% to 1.0 wt% triethyl citrate, 4wt% to 8wt% talc, 0.5wt% to 1.5wt% silicon dioxide.

[0114] Most preferably, the present invention is directed to an oral formulation as described above, wherein each particle is in the form of a coated mini-tablet, and Each particle consists of: 9.22 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, 4.06 wt% HPMCAS, 22.12 wt% low-substituted hydroxypropyl cellulose, 2.77 wt% hydroxypropyl cellulose, 23.04 wt% croscarmellose sodium, 23.04 wt% mannitol, 0.64 wt% triethyl citrate, 8.3 wt% adipic acid, 0.07 wt% ammonium bicarbonate, 5.83 wt% talc, and 0.92 wt% silicon dioxide, or Each particle consists of: 10.05 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, 4.42 wt% HPMCAS, 24.12 wt% low-substituted hydroxypropyl cellulose, 3.02 wt% hydroxypropyl cellulose, 25.13 wt% croscarmellose sodium, 25.13 wt% mannitol, 0.69 wt% triethyl citrate, 0.08 wt% ammonium bicarbonate, 6.35 wt% talc, and 1.01 wt% silicon dioxide, or Each particle consists of: 9.22 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, 3.74 wt% Eudragit® L100; 0.66 wt% Eudragit® S100; 22.12 wt% low-substituted hydroxypropyl cellulose, 2.76 wt% hydroxypropyl cellulose, 23.04 wt% croscarmellose sodium, 23.04 wt% mannitol, 0.43 wt% triethyl citrate, 8.29 wt% adipic acid, 5.76 wt% talc, and 0.92 wt% silicon dioxide, or Each particle consists of: 10.05 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, 4.08 wt% Eudragit® L100; 0.72 wt% Eudragit® S100; 24.12 wt% low-substituted hydroxypropyl cellulose, 3.02 wt% hydroxypropyl cellulose, 25.13 wt% croscarmellose sodium, 23.13 wt% mannitol, 0.47 wt% triethyl citrate, 6.28 wt% talc, and 1.01wt% silicon dioxide.

[0115] In other embodiments, the oral formulation of the present invention comprises a core material in the form of a core pellet consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose.

[0116] Thus, in some embodiments, the present invention refers to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, or coated minicapsules, each particle being (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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), a core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or a microcrystalline cellulose core material; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0117] Preferably, the core material consists of microcrystalline cellulose in the form of core pellets. Preferably, the enteric coating polymer is selected from the group comprising or consisting of: methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the foregoing enteric coating polymers.

[0118] The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0119] In some embodiments, the present invention refers to an oral formulation, wherein the particles are in the form of coated granules, coated pellets, coated beads, or coated minicapsules, and the core material in the form of the core pellets consists of the following: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline.

[0120] In some embodiments, the present invention is directed to oral formulations, where the particles are in the form of coated granules, coated pellets, coated beads, or coated minicapsules, and the core material in the form of the core pellets consists of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline, and Here, the core pellets are coated with (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 an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, together with at least one binder, colorant, flow agent, surfactant and / or filler.

[0121] In some embodiments, in the oral formulations described above, the enteric coating polymer is included in or forms the outer layer of the coating that surrounds the core material. Thus, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, or coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), A core material in the form of a core pellet selected from the group consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, and microcrystalline cellulose, preferably microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the enteric coating polymer is included in or forms the outer layer of the coating that surrounds the core material.

[0122] Oral formulations comprising a core material in the form of core pellets as described herein may further comprise at least one binder, colorant, flow agent, surfactant and / or filler.

[0123] Thus, in some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0124] Preferably, the core material is in the form of core pellets made of microcrystalline cellulose, more preferably Cellets. Cellet is a highly spherical core pellet made of 100% microcrystalline cellulose. The size of the microcrystalline cellulose core pellet can range from 100 μm to 200 μm (Cellet 100), 200 μm to 355 μm (Cellet 200), 350 μm to 500 μm (Cellet 350), 500 μm to 710 μm (Cellet 500), 700 μm to 1000 μm (Cellet 700) and 1000 μm to 14000 μm (Cellet 1000). More preferably, the particle size of the microcrystalline cellulose core pellet ranges from 200 μm to 710 μm (Cellet 200, 350, 500), even more preferably from 350 μm to 710 μm (Cellet 350, 500), and most preferably from 500 μm to 710 μm (Cellet 500).

[0125] In some embodiments, the present invention refers to an oral formulation, wherein the core material is in the form of a core pellet as described above, and the size of the core pellet ranges from 100 μm to 14000 μm.

[0126] In some embodiments, the present invention refers to an oral formulation, wherein the core material is in the form of a core pellet as described above, the core pellet is made of microcrystalline cellulose, and the size of the core pellet ranges from 500 μm to 710 μm (Cellette 500).

[0127] As used herein, the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof.

[0128] As used herein, the surfactant is preferably an anionic surfactant and contains an anionic functional group, such as sulfate, sulfonate, phosphate, and carboxylate. Preferably, the anionic surfactant includes, but is not limited to, ammonium lauryl sulfate, sodium dodecyl sulfate (sodium lauryl sulfate), sodium laureth sulfate, and sodium myreth sulfate, preferably sodium dodecyl sulfate.

[0129] Preferably, the oral formulation is such that the core material is in the form of a core pellet as described above, and said oral formulation further comprises at least one binder, colorant, flow agent, surfactant and / or filler, where The binder is polyvinylpyrrolidone (povidone); the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate.

[0130] Thus, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: (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 of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, where The binder is polyvinylpyrrolidone (povidone); the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0131] Povidone K25, Povidone K30, or Povidone K90 are commercially available, and preferably Povidone K25 is used as the binder. The approximate average molecular weight of Povidone K25 is 30,000 g / mol (Da) between 28,000 g / mol (Da) and 34,000 g / mol (Da).

[0132] In oral formulations comprising a core material in the form of core pellets as described herein, the layer comprising the enteric coating polymer may further comprise at least one buffering agent, plasticizer, and / or flow agent.

[0133] Thus, in some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or flow agent.

[0134] Preferably, the buffer is ammonium bicarbonate; The plasticizer is triethyl citrate, and / or The flow agent is talc.

[0135] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, where The binder is polyvinylpyrrolidone (povidone); the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or flow agent.

[0136] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, where The binder is polyvinylpyrrolidone (povidone); Coloring agents are titanium dioxide, iron(III) oxide, iron(II,III) oxide, ferric oxide hydrate, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or flow agent; Where: The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The flow agent is talc.

[0137] Preferably, it is an oral formulation, wherein the core material is in the form of a core pellet as previously described and comprises a binder, a colorant, a surfactant, a filler, a buffer, a plasticizer, and / or a flow agent; and The binder is Povidone K25. the coloring agent is selected from titanium dioxide, titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; The filler is lactose monohydrate, The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The flow agent is talc.

[0138] Thus, in some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, where The binder is polyvinylpyrrolidone (povidone); Coloring agents are titanium dioxide, iron(III) oxide, iron(II,III) oxide, ferric oxide hydrate, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or flow agent; Where: The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The flow agent is talc.

[0139] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle is: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, and At least one coating layer comprising or consisting of an enteric coating polymer; a plurality of particles comprising at least one buffering agent, plasticizer, and / or flow agent; Here, each particle is coated with at least one coating layer.

[0140] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate, wherein the core material is coated with at least one layer, At least one coating layer comprising or consisting of an enteric coating polymer; a plurality of particles comprising at least one buffering agent, plasticizer, and / or flow agent; Where: The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The superplasticizer is talc, Here, each particle is coated with at least one coating layer.

[0141] In another embodiment, the present invention refers to an oral formulation as described above, wherein each particle is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0142] Thus, in some embodiments, the present invention refers to an oral formulation adapted for the selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, or coated minicapsules, Each particle: (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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), A core material in the form of a core pellet, the core material consisting of: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and is further coated with a coating layer comprising or consisting of a sustained release polymer. The sustained release polymer may be first coated under a coating layer comprising or consisting of the enteric coating polymer, or the sustained release polymer may be subsequently coated on top of a coating layer comprising or consisting of the enteric coating polymer.

[0143] Preferably, the sustained release polymer is selected from hypromellose (HPMC), ethylcellulose, ammonio methacrylate copolymers such as Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5, and the like, and mixtures thereof. When the sustained release polymer is ethylcellulose, optionally polyethylene glycol (PEG) is further included as a plasticizer, preferably Macrogol® 6000.

[0144] Hypromellose (HPMC) may be first coated under a coating layer comprising or consisting of an enteric coating polymer. Ethylcellulose, Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5 may be subsequently coated on top of a coating layer comprising or consisting of an enteric coating polymer. When the sustained release polymer is ethylcellulose, optionally polyethylene glycol (PEG) is further included as a plasticizer, preferably Macrogol® 6000.

[0145] Ammonio methacrylate copolymers such as Eudragit® RL100 and Eudragit® RS100 may be suitable for use in the modified release formulations of the present invention. These polymers are insoluble in pure water, dilute acid, buffers, or digestive fluids over the entire physiological pH range. The polymers swell in water and digestive fluids regardless of pH. In the swollen state, the polymers then become permeable to water and dissolved active agents. The permeability of the polymers depends on the ratio of ethyl acrylate (EA), methyl methacrylate (MMA), and trimethylammonioethyl methacrylate chloride (TAMCl) groups in the polymer. Those polymers with a ratio of EA:MMA:TAMC1 of 1:2:0.2 (Eudragit® RL100) are more permeable than those polymers with a ratio of 1:2:0.1 (Eudragit® RS100). The Eudragit® RL100 polymer is a highly permeable insoluble polymer. The polymer of Eudragit® RS100 is an insoluble film with low permeability.

[0146] Ammonio methacrylate copolymers can be combined in any desired ratio, and the ratio can be modified to modify the drug release rate. For example, a ratio of 90:10 Eudragit® RS100:Eudragit® RL100 can be used. Alternatively, the ratio of Eudragit® RS100:Eudragit® RL100 can be about 100:0 to about 80:20, or about 100:0 to about 90:10, or any ratio therebetween. In the formulation, the Eudragit® RS100, which is a polymer with low permeability, generally constitutes the majority of the polymeric material, with the RL with high permeability, which allows and creates interstices through which solutes can enter the core and dissolved pharmacoactive ingredients can exit in a controlled manner.

[0147] Ammonio methacrylate copolymers can be combined with methacrylic acid copolymers within the polymeric material to achieve the desired delay in drug release. Ratios of amino methacrylate copolymer (e.g., Eudragit® RS100) to methacrylic acid copolymer ranging from about 99:1 to about 20:80 can be used. The two polymers can be combined in the same polymeric material or provided as separate coatings applied to the core.

[0148] Eudragit® RL12.5 and Eudragit® RL100 are ammonio methacrylate copolymers (type A)=poly[ethylpropanoate-co-methyl 2-methylprop-2-enoate-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethane-1-aminium chloride] with an average relative molecular weight of about 150,000. The ratio of ethyl acrylate groups to methyl methacrylate groups to ammonio methacrylate groups is about 1:2:0.2.

[0149] Eudragit® RS12.5 and Eudragit® RS100 are ammonio methacrylate copolymers (type B)=poly[ethylpropanoate-co-methyl 2-methylprop-2-enoate-co-N,N,N-trimethyl-2-[(2-methylprop-2-enoyl)oxy]ethane-1-aminium chloride] with an average relative molecular weight of about 150,000. The ratio of ethyl acrylate groups to methyl methacrylate groups to ammonio methacrylate groups is about 1:2:0.1.

[0150] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0151] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: (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 of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is first coated with a coating layer comprising or consisting of a sustained release polymer, and subsequently further coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0152] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, a coating layer comprising or consisting of a sustained release polymer; and At least one coating layer comprising or consisting of an enteric coating polymer; a plurality of particles comprising at least one buffering agent, plasticizer, and / or flow agent; Here, each particle is coated with at least one layer. Here, each core material is first coated with a coating layer comprising or consisting of a sustained release polymer, and then further coated with at least one coating layer comprising or consisting of an enteric coating polymer.

[0153] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I), with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0154] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle is: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. a coating layer comprising or consisting of a sustained release polymer; and At least one coating layer comprising or consisting of an enteric coating polymer; a plurality of particles comprising at least one buffering agent, plasticizer, and / or flow agent; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0155] Preferred are those oral formulations, in which each core material is first coated with a coating layer comprising or consisting of a sustained release polymer, and subsequently further coated with at least one coating layer comprising or consisting of an enteric coating polymer, or Here, each core material is first coated with at least one coating layer comprising or consisting of an enteric coating polymer, followed by a coating layer comprising or consisting of a sustained release polymer.

[0156] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or glidant, and each particle is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0157] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle is: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, At least one coating layer comprising or consisting of an enteric coating polymer; at least one buffering agent, plasticizer, and / or flow agent; A plurality of particles comprising a coating layer comprising or consisting of a sustained release polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0158] Preferred are these oral formulations, in which each core material is first coated with a coating layer comprising or consisting of a sustained release polymer, and subsequently further coated with at least one coating layer comprising or consisting of an enteric coating polymer, or Here, each core material is first coated with at least one coating layer comprising or consisting of an enteric coating polymer, followed by a coating layer comprising or consisting of a sustained release polymer.

[0159] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or glidant, and each particle is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0160] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. At least one coating layer comprising or consisting of an enteric coating polymer; at least one buffering agent, plasticizer, and / or flow agent; A plurality of particles comprising a coating layer comprising or consisting of a sustained release polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0161] Preferred are these oral formulations, in which each core material is first coated with a coating layer comprising or consisting of a sustained release polymer, and subsequently further coated with at least one coating layer comprising or consisting of an enteric coating polymer, or Here, each core material is first coated with at least one coating layer comprising or consisting of an enteric coating polymer, followed by a coating layer comprising or consisting of a sustained release polymer.

[0162] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle: (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 of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I). with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; wherein each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and the layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or flow agent; Where: The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The superplasticizer is talc, and Each particle is further coated with a coating layer comprising or consisting of a sustained release polymer, preferably the sustained release polymer is selected from hypromellose (HPMC), ethylcellulose, ammonio methacrylate copolymers such as Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5, and mixtures thereof. When the sustained release polymer is ethylcellulose, optionally polyethylene glycol (PEG) is further included as a plasticizer, preferably Macrogol® 6000.

[0163] In some embodiments, an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal comprises or consists of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle is A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; At least one layer 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-carboxamide)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant and / or filler, Where: The binder is polyvinylpyrrolidone (povidone); the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, and / or The filler is lactose monohydrate. At least one coating layer comprising or consisting of an enteric coating polymer; at least one buffering agent, plasticizer, and / or flow agent; Where: The buffer is ammonium bicarbonate. The plasticizer is triethyl citrate, and / or The flow agent is talc, A plurality of particles comprising a coating layer comprising or consisting of a sustained release polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer, and is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0164] Preferred are these oral formulations, in which each core material is first coated with a coating layer comprising or consisting of a sustained release polymer, and subsequently further coated with at least one coating layer comprising or consisting of an enteric coating polymer, or Here, each core material is first coated with at least one coating layer comprising or consisting of an enteric coating polymer, followed by a coating layer comprising or consisting of a sustained release polymer.

[0165] Preferably, the oral formulation disclosed herein is comprised of: coated granules, coated pellets, coated beads, coated minicapsules, wherein Each particle contains: 5 wt% to 15 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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), 30 wt % to 55 wt % of a core material consisting of tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose; and 15wt% to 30wt% of the enteric coating polymer.

[0166] In some embodiments, the present invention is directed to an oral formulation adapted for selective delivery of Compound 1 to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, Each particle is: 5 wt% to 15 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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), 15 wt% to 30 wt% of an enteric coating polymer; a plurality of particles comprising 30 wt% to 55 wt% of a core material consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, and preferably microcrystalline cellulose; Here, each particle is further coated with a coating layer comprising or consisting of a sustained release polymer.

[0167] Preferably, the oral formulations described herein are comprised of: multiple particles in the form of coated granules, coated pellets, coated beads, coated minicapsules; Where: Each particle contains: 5 wt. % to 15 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 of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), and 30wt% to 55wt% of the core material, and 15 wt% to 30 wt% of an enteric coating polymer, and 0.1 wt% to 2.0 wt% sustained release polymer.

[0168] Further preferred is an oral formulation as described herein, which comprises: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of a core pellet and consists of microcrystalline cellulose; Each particle contains: 5 wt% to 15 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, 30wt% to 45wt% microcrystalline cellulose; 15wt% to 25wt% HPMCAS, 10wt% to 20wt% lactose monohydrate, 10wt% to 15wt% talc, 1.0 wt% to 3.0 wt% triethyl citrate; 0.1 wt% to 1.0 wt% ammonium bicarbonate, and Optionally, 0.1 wt % to 2.0 wt % sodium dodecyl sulfate, and / or 0.1wt% to 2.0wt% HPMC.

[0169] Preferably, the oral formulation as described herein is made up of: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of core pellets and consists of microcrystalline cellulose; Each particle contains: 30wt% to 45wt% microcrystalline cellulose core as the core material; At least one layer comprising or consisting of: 5 wt% to 15 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, 30wt% to 45wt% microcrystalline cellulose core; 10wt% to 20wt% lactose monohydrate, optionally, 0.1 wt % to 2.0 wt % sodium dodecyl sulfate; At least one coating layer comprising or consisting of: 15wt% to 25wt% HPMCAS, 10wt% to 15wt% talc, 1.0 wt% to 3.0 wt% triethyl citrate, and 0.1wt% to 1.0wt% ammonium bicarbonate, and / or A coating layer comprising or consisting of: 0.1 wt% to 2.0 wt% HPMC as a sustained release polymer, where each particle is coated with at least one coating layer comprising or consisting of HPMCAS and further coated with a coating layer comprising or consisting of HPMC.

[0170] Preferably, each core material is first coated with a coating layer comprising or consisting of HPMC, followed by at least one further coating layer comprising or consisting of HPMCAS.

[0171] Preferred is further the oral formulation as described herein, consisting of a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of core pellets and consists of microcrystalline cellulose, Each particle contains: 5 wt% to 15 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, 30wt% to 45wt% microcrystalline cellulose core; 15wt% to 30wt% Eudragit® L100 and 0wt% to 5wt% Eudragit® S100; 10wt% to 20wt% lactose monohydrate, 10wt% to 15wt% talc, 0.5 wt% to 2.0 wt% Povidone K25, 1.0 wt% to 3.0 wt% triethyl citrate, and / or Optionally, 0.1 wt % to 2.0 wt % ethylcellulose, and PEG, preferably the PEG is Macrogol® 6000.

[0172] Preferably, each core material is first coated with a coating layer comprising or consisting of Eudragit® L100 and Eudragit® S100, followed by at least one further coating layer comprising or consisting of ethylcellulose and PEG.

[0173] Further preferred is an oral formulation as described herein, which comprises: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of a core pellet and consists of microcrystalline cellulose; Each particle contains: 30wt% to 45wt% microcrystalline cellulose core as the core material; At least one layer comprising or consisting of: 5 wt% to 15 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, 10wt% to 20wt% lactose monohydrate, 0.5 wt% to 2.0 wt% Povidone K25, At least one coating layer comprising or consisting of: 15wt% to 30wt% Eudragit® L100, and 0 wt% to 5 wt% Eudragit® S100, 10wt% to 15wt% talc, 1.0 wt% to 3.0 wt% triethyl citrate, and / or Optionally, A coating layer comprising or consisting of 0.1 wt % to 2.0 wt % ethylcellulose, and PEG, preferably the PEG is Macrogol (registered trademark) 6000.

[0174] Preferably, each core material is first coated with a coating layer comprising or consisting of Eudragit® L100 and Eudragit® S100, and then further coated with at least one coating layer comprising or consisting of ethylcellulose and PEG, preferably the PEG being Macrogol® 6000.

[0175] Further preferred is an oral formulation as described herein, which comprises: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of a core pellet and consists of microcrystalline cellulose; Each of the particles comprises: 7 wt.% to 12 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, 37 wt% to 41 wt% microcrystalline cellulose core (Cellette 500); 15wt% to 19wt% HPMCAS, 14 wt% to 18 wt% lactose monohydrate, 11wt% to 15wt% talc, 0.5 wt% to 2.0 wt% Povidone K25, 1.0 wt% to 3.0 wt% triethyl citrate, and 0.1wt% to 1.0wt% ammonium bicarbonate, or The particles consist of: 7 wt.% to 12 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, 37 wt% to 41 wt% microcrystalline cellulose core (Cellette 500); 15wt% to 19wt% HPMCAS, 12wt% to 16wt% lactose monohydrate, 11wt% to 15wt% talc, 0.5 wt% to 2.0 wt% Povidone K25, 1.0 wt% to 3.0 wt% triethyl citrate; 0.5 wt% to 2.0 wt% sodium dodecyl sulfate, and 0.1wt% to 1.0wt% ammonium bicarbonate, or The particles consist of: 7 wt.% to 12 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, 37 wt% to 41 wt% microcrystalline cellulose core (Cellette 500); 15wt% to 19wt% HPMCAS, 13wt% to 17wt% lactose monohydrate, 11wt% to 15wt% talc, 0.5 wt% to 2.0 wt% Povidone K25, 1.0 wt% to 3.0 wt% triethyl citrate; 0.1 wt% to 1.0 wt% ammonium bicarbonate, and 0.5wt% to 2.0wt% HPMC, or The particles consist of: 7 wt.% to 12 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, 33wt% to 37wt% microcrystalline cellulose core (Cellette 500); 20 wt% to 24 wt% Eudragit® L100 and 3 wt% to 5 wt% Eudragit® S100; 12wt% to 16wt% lactose monohydrate, 12 wt% to 15 wt% talc, and 1.0 wt% to 3.0 wt% triethyl citrate; or The particles consist of: 7 wt.% to 12 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, 35 wt% to 39 wt% microcrystalline cellulose core (Cellette 200); 23 wt% to 27 wt% Eudragit® L100; 10 wt% to 14 wt% lactose monohydrate, 12wt% to 15wt% talc, 1.0 wt% to 3.0 wt% triethyl citrate; 0.01 wt% to 0.5 wt% ethylcellulose, and 0.01 wt% to 0.5 wt% Macrogol® 6000.

[0176] Further preferred is an oral formulation as described herein, which comprises: a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, wherein the core material is in the form of a core pellet and consists of microcrystalline cellulose; The particles consist of: 9.80 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, 39.19 wt% microcrystalline cellulose core (Cellett 500); 17.57 wt% HPMCAS, 15.58 wt% lactose monohydrate, 13.11 wt% talc, 1.67 wt% Povidone K25, 2.76 wt% triethyl citrate, and 0.33 wt% ammonium bicarbonate, or The particles consist of: 9.80% 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, 39.19 wt% microcrystalline cellulose core (Cellett 500); 17.57 wt% HPMCAS, 14.40 wt% lactose monohydrate, 13.11 wt% talc, 1.49 wt% Povidone K25, 2.76 wt% triethyl citrate, 1.35 wt% sodium dodecyl sulfate, and 0.33 wt% ammonium bicarbonate, or The particles consist of: 9.68 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, 38.70 wt% microcrystalline cellulose core (Ceret 500); 17.57 wt% HPMCAS, 15.38 wt% lactose monohydrate, 13.01 wt% talc, 1.64 wt% Povidone K25, 2.76 wt% triethyl citrate, 0.33 wt% ammonium bicarbonate, and 0.92 wt% HPMC, or The particles consist of: 8.89 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, 34.75 wt% microcrystalline cellulose core (Ceret 500); 21.44 wt% Eudragit® L100, and 3.78 wt% Eudragit® S100; 13.81 wt% lactose monohydrate, 13.55 wt% talc, and 2.55 wt% triethyl citrate, or The particles consist of: 7.93 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, 37.58 wt% microcrystalline cellulose core (Ceret 500); 24.86 wt% Eudragit® L100; 12.61 wt% lactose monohydrate, 13.01 wt% talc, 2.48 wt% triethyl citrate, 0.12 wt% ethyl cellulose, and 0.06 wt% Macrogol® 6000.

[0177] In some preferred embodiments, in any of the oral formulations of the invention described herein, the enteric coating polymer is dissolved at a pH value ranging from 5.0 to 7.5, preferably from 5.0 to 7.0, more preferably from 5.5 to 7.0, and most preferably from 5.5 to 6.8.

[0178] In some preferred embodiments, in any of the oral formulations of the present invention described herein, the size of each particle ranges from 0.5 mm to 5 mm. Coated minitablets are preferably 1 mm to 4 mm in size. Oral formulations in the form of coated granules, coated pellets, coated beads, coated minicapsules have a size of each particle ranging from 0.5 mm to 1.3 mm, preferably 0.6 mm to 1.2 mm, more preferably 0.7 mm to 1.1 mm, more preferably 0.8 mm to 1.0 mm.

[0179] In some preferred embodiments, in any of the oral formulations of the invention described herein, the plurality of particles is contained in a capsule, sachet, or stick pack, or is formed as a tablet. Thus, the oral formulation of the invention is in the form of a capsule, sachet, or stick pack, or a tablet. [Instructions]

[0180] Surprisingly, the oral solid formulation of the present invention has been shown to exhibit gastric resistance and release (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 an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, in the ileum after a certain delay time required for the formulation to pass or transit through the stomach and duodenum.

[0181] To ensure local availability in the ileum, drug release should already begin in the jejunum. Gastro-resistant oral solid formulations utilizing the described release profile are also often classified as delayed release dosage forms. Delayed release dosage forms require a specific trigger for drug release, such as a target pH value or an enzyme. Time-dependent release is also an option to promote delay. A preferred embodiment of the present invention refers to an oral solid dosage form that releases drug in the jejunum and ileum after reaching a specific pH value. The pH value that triggers release should be in the range of 6.2 to 6.8.

[0182] Oral solid formulations suitable for delayed release can include either single-unit non-disintegrating dosage forms such as tablets, or disintegrating dosage forms comprising multiple-unit granules / pellets / beads, also known as multiple-unit pellet systems or MUPS.Embodiments according to the invention are preferably multiparticulate dosage forms, which offer several advantages over non-disintegrating dosage forms, such as predictable residence times in the stomach in fasted and fed states with low risk of dose dumping, reliable and robust release patterns, due to the homogeneous distribution of drug across a relatively high particle surface, and the possibility to flexibly vary the units into a variety of different dose strengths. The term granules / pellets / beads as used herein refers to relatively small spherical particles having a diameter ranging from about 0.2 to about 1.8 mm, preferably from about 0.5 to about 1.5 mm, the spherical particles 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 an enantiomer, solvate, hydrate or a pharma-ceutically acceptable salt thereof, and suitable excipients.

[0183] One embodiment of the present invention relates to a systemic formulation for use in the prevention and / or treatment of fibrostenosing Crohn's disease 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-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt thereof, wherein the systemic formulation is in the form of an enteral formulation.

[0184] The enteral formulation is preferably an oral solid formulation for modifying drug release, i.e., delivering (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 an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, to the proximal and distal ileum. Ileum targeting refers to the property of an oral formulation to promote local availability and local action 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 an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, in a given portion of the small intestine and to avoid premature release in the upper part of the gastrointestinal tract (i.e., stomach and duodenum).

[0185] In some embodiments, the present invention is directed to an oral formulation of the present invention for use in the prevention and / or treatment of intestinal fibrosis.

[0186] Preferably, for use in the prevention and / or treatment of intestinal fibrosis, the oral formulation is adapted to initiate release 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, enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt thereof in the jejunum and complete release in the ileum.

[0187] Preferably, the oral formulation is useful for the prevention and / or treatment of fibrostenosing Crohn's disease. [Preparation method]

[0188] In another aspect, the present invention refers to a method for preparing the oral formulation described above, comprising: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0189] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

[0190] Optionally, the preparation method further comprises step C): Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0191] In some embodiments, steps A)-B)-C) are performed. Alternatively, steps A)-C)-B) can be performed. Thus, in some embodiments, the present invention refers to a method for preparing the oral formulation described above, comprising: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0192] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, Step B) coating each particle with at least one coating solution comprising an enteric coating polymer; and Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0193] Alternatively, the method for preparing the oral formulation described above includes: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0194] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and Core material, Step C) coating each particle with a coating solution containing a sustained release polymer; and Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

[0195] Preferably, in the process according to the invention, when the particles are in the form of coated mini-tablets, the core material comprises one or more binders, disintegrants, flow agents, pH-adjusting agents and / or fillers. pH-adjusting agents may optionally be used. More preferably, the core material comprises one or more binders, disintegrants, flow agents, pH-adjusting agents, and / or fillers; and the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K25, or a mixture thereof; The disintegrant is croscarmellose sodium. The flow agent is talc, and / or The bulking agent is mannitol, lactose monohydrate, or a mixture thereof.

[0196] Even more preferably, the core material comprises one or more binders, disintegrants, flow agents, pH-adjusting agents, and / or fillers; and the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K25, or a mixture thereof; The disintegrant is croscarmellose sodium. The superplasticizer is talc, The pH-adjusting agent is adipic acid, and / or The bulking agent is mannitol, lactose monohydrate, or a mixture thereof.

[0197] In another aspect, the present invention is directed to a method for preparing an oral formulation comprising a core material in the form of a core pellet consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose, preferably microcrystalline cellulose.

[0198] Thus, in some embodiments, the present invention refers to a method for preparing an oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, or coated minicapsules, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I) or an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt of formula (I), A core material in the form of a core pellet, the core material consisting of: tartaric acid, lactose, sugar, corn starch, starch hydrolysate, silica, or microcrystalline cellulose; and a plurality of particles comprising an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of an enteric coating polymer. Preferably, the core material consists of microcrystalline cellulose in the form of core pellets.

[0199] Thus, the present invention refers to a method for preparing said oral formulation, Includes: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0200] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; and Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

[0201] Optionally, the preparation method further comprises step C): Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0202] In some embodiments, steps A)-B)-C) are performed. Alternatively, steps A)-C)-B) can be performed. Thus, in some embodiments, the present invention refers to a method for preparing the oral formulation described above, comprising: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0203] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose. Step B) coating each particle with at least one coating solution comprising an enteric coating polymer; and Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0204] Alternatively, the method for preparing the oral formulation described above includes: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I)

[0205] [ka] or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, and A core material in the form of a core pellet, comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; Step C) coating each particle with a coating solution containing a sustained release polymer; and Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

[0206] Preferably, the core material consists of tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose in the form of a core pellet, and the core material is coated with (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, an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt thereof together with at least one binder, colorant, flow agent, surfactant, and / or filler.

[0207] Hypromellose (HPMC) may be first coated under a coating layer comprising or consisting of an enteric coating polymer, followed by coating of ethylcellulose, Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5 on top of the coating layer comprising or consisting of the enteric coating polymer. When the sustained release polymer is ethylcellulose, it optionally further comprises polyethylene glycol (PEG) as a plasticizer, preferably Macrogol® 6000.

[0208] Therefore, step A) may be replaced by the following steps A-1) and A-2), and the oral formulation of the present invention can be prepared as follows: Step A-1) providing a core material in the form of a plurality of core pellets, the core material comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; Step A-2) coating with a solution containing (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), an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant, and / or filler; Obtaining a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules; Step B) coating each particle with at least one coating solution comprising an enteric coating polymer, and optionally Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0209] Alternatively, the oral formulation of the present invention can be prepared as follows: Step A-1) providing a core material in the form of a plurality of core pellets, the core material comprising: tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose; Step A-2) coating with a solution containing (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), an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant, and / or filler; Obtaining a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules; Step C) coating each particle with a coating solution containing a sustained release polymer; and Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

[0210] Preferably, in step A-1), the core material is in the form of core pellets and consists of microcrystalline cellulose, more preferably the particle size of the microcrystalline cellulose core pellets ranges from 100 μm to 355 μm (Cellett 100, Cellett 200).

[0211] Thus, step A) may be replaced by the following steps A-1) and A-2), and the oral formulation of the present invention may be prepared as follows: Step A-1) providing a core material in the form of a plurality of core pellets, the core material being comprised of microcrystalline cellulose, more preferably Celeto 100, Celeto 200, Celeto 350, or Celeto 500; Step A-2) coating with a solution containing (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), an enantiomer, solvate, hydrate, or a pharma- ceutically acceptable salt of formula (I) together with at least one binder, colorant, flow agent, surfactant, and / or filler; Obtaining a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules; Step B) coating each particle with at least one coating solution comprising an enteric coating polymer, and optionally Step C) Coating each particle with a coating solution containing a sustained release polymer.

[0212] In some embodiments, in the above method, The binder is Povidone K25. the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; The surfactant is sodium dodecyl sulfate. The flow agent is talc, and / or The filler is lactose monohydrate.

[0213] In some embodiments, in step B) of the method described above, the one or more coating solutions further comprise at least one buffering agent, plasticizer, and / or flow agent. Preferably, the buffer is ammonium bicarbonate; The plasticizer is triethyl citrate, and / or The flow agents are talc, silicon dioxide, and mixtures thereof.

[0214] In some preferred embodiments, in step B) of the above-described method, the enteric coating polymer is selected from the group consisting of methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the aforementioned enteric coating polymers. The hypromellose acetate succinate is preferably selected from the group consisting of: hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of: Eudragit® L100, Eudragit® S100, and mixtures thereof.

[0215] In some embodiments, in step B) of the method described above, water or a mixture of water and isopropyl alcohol is used to prepare one or more coating solutions.

[0216] In some preferred embodiments, in step C) of the above-described method, the sustained release polymer is selected from hypromellose (HPMC), ethylcellulose, ammonio methacrylate copolymer, such as Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5, or mixtures thereof, preferably hypromellose (HPMC).

[0217] When the sustained release polymer is ethylcellulose, it optionally further comprises polyethylene glycol (PEG) as a plasticizer, preferably Macrogol® 6000.

[0218] When step C) is performed after step B), the coating solution comprises a sustained release polymer selected from ethyl cellulose, ammonio methacrylate copolymer, such as Eudragit® RL100, Eudragit® RS100, Eudragit® RL12.5, Eudragit® RS12.5, etc., or mixtures thereof, preferably ethyl cellulose, and mixtures thereof. When the sustained release polymer is ethyl cellulose, it optionally further comprises polyethylene glycol (PEG) as a plasticizer, preferably Macrogol® 6000.

[0219] When step C) is performed before step B), the coating solution contains hypromellose (HPMC) as the sustained release polymer.

[0220] The embodiment according to the present invention refers to delayed release granules / pellets / beads obtained by a continuous two-step coating process in a fluidized bed system. The inert starter granules / pellets / beads are transferred to the fluidized bed of the coater and sprayed with the coating solution or the feed solution. The inert starter granules / pellets / beads are neutral uniform spherical materials for coating and layering. The spherical materials are available in various but reproducible sizes. The inert starter granules / pellets / beads include tartaric acid core pellets, lactose core pellets, sugar core pellets, silica core pellets, and microcrystalline cellulose core pellets. Preferably, the core pellets are microcrystalline cellulose pellets. The size of the microcrystalline cellulose core pellets can range from 100 μm to 200 μm (Cellet 100), 200 μm to 355 μm (Cellet 200), 350 μm to 500 μm (Cellet 350), 500 μm to 710 μm (Cellet 500), 700 μm to 1000 μm (Cellet 700), and 1000 μm to 1400 μm (Cellet 1000). Preferably, the particle size of the microcrystalline cellulose core pellets ranges from 500 μm to 710 μm (Cellet 500). More preferably, the particle size of the microcrystalline cellulose core pellets is in the range of 200 μm to 710 μm (Cellet 200, 350, 500), even more preferably in the range of 350 μm to 710 μm (Cellet 350, 500), and most preferably in the range of 500 μm to 710 μm (Cellet 500). [Brief description of the drawings]

[0221] [Figure 1] Figure 1 shows the in vitro dissolution profile of Compound 1 (50 mg) from delayed release granules. Drug layered granules with 35% HPCMAS refer to HPCMAS-HF, and drug layered granules with 35% Eudragit® L / S refer to Eudragit® L100 / S100. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0222] [Example]

[0223] Preparation procedure 1. Preparation method 1 1.1. Preparation of Granules / Pellets / Beads: One or more coatings can be layered on the neutral core pellets in the fluidized bed. During this process, each coating forms a thin film or layer that adheres to the surface of the pellet. Each layer can provide a specific function to the granule / pellet / bead, such as layering, sealing, protection, controlled release, taste masking, or improved swallowability. In a preferred embodiment, the inert core pellets are layered with (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 pharma- ceutically acceptable salt, binder, filler, and lubricant / flow agent to obtain drug-layered pellets. The inert core pellets are sprayed with a coating solution, or feed solution, consisting of solute and solvent in a preferred ratio of 25% w / w solute to 75% w / w solvent. The solute 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-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate or pharma- ceutically acceptable salt thereof, Povidone K25 used as a binder, lactose monohydrate used as a filler, and glycerol used as a lubricant / flow enhancer. The talc used comprises a preferred ratio of about 28% (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 an enantiomer, solvate, hydrate or pharma-ceutically acceptable salt thereof, 5% povidone K25, 45% lactose monohydrate, and 23% talc.

[0224] The solvent of the spray or feed solution is a binary mixture of isopropyl alcohol and purified water at 20% w / w (isopropyl alcohol) and 80% w / w (purified water). After the coating step, the mass of the pellets has increased by about 90% (weight gain) and the drug (compound 1) concentration of the granules / pellets / beads is about 132 mg / g (i.e., 13.2%). A quantitative summary of the drug-layered granules / pellets / beads is shown below:

[0225] [Table 2]

[0226] The drug layered granules / pellets / beads can be further coated with a sealing layer to protect the surface of the particles from chemical or physical stress, or a layer to mask the taste or improve the ease of swallowing the pellets. Usually, excipients are used, such as derivatives of cellulose, cellulose ethers, such as hydroxypropylmethylcellulose (HMPC), synthetic polymers, shellac, corn protein zein, or other polysaccharides, and aminomethacrylate copolymers. The coating can further include colorants, titanium dioxide, iron (III) oxide, iron (II, III) oxide, or hydrated ferric oxide, lactose monohydrate, and or carnauba wax. The layered granules / pellets / beads can be provided in different dosage strengths by encapsulating the required amount of pellets in hard capsules or by filling the required amount of pellets in sachets or stick packs. These products are fast-acting, conventional, or immediate release dosage forms.

[0227] Preferably, the drug-layered granules / pellets / beads are further coated with at least one release modifying polymer to obtain the required delayed release profile, the release modifying polymer being selected from the group consisting of hypromellose acetate succinate (HPMCAS), hypromellose phthalate, methacrylic acid-methyl methacrylate copolymer, methacrylic acid-ethyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, or mixtures thereof. The coating may further include buffers, plasticizers, flow agents / lubricants, and colorants, such as titanium dioxide, iron (III) oxide, iron (II, III) oxide or ferric oxide hydrate, lactose monohydrate, and / or carnauba wax. Particularly preferred are enteric coating polymers of hypromellose acetate succinate (HPMCAS), available in various grades, such as HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof, preferably HPMCAS-HF, HPMCAS-HMP, more preferably HPMCAS-HF, and methacrylic acid-methyl methacrylate copolymers, either alone or in combination at various concentrations. These coatings may also further include buffers, plasticizers, flow agents / lubricants, and colorants, such as titanium dioxide, iron (III) oxide, iron (II, III) oxide or ferric oxide hydrate, lactose monohydrate, and / or carnauba wax.

[0228] 1.2. Preparation of enteric polymer coated granules / pellets / beads:

[0229] 1.2.1 Preparation of HPMCAS coated granules / pellets / beads The drug layered pellets are coated with a coating or feed solution consisting of solutes and solvents in a preferred ratio of 10% w / w solute to 90% w / w solvent. The solutes include a four-component mixture of HPMCAS used as an enteric polymer, ammonium bicarbonate (NH4HCO3) used as a buffer, triethyl citrate used as a plasticizer, and talc used as a flow agent / lubricant in a preferred ratio of about 68% HPMCAS, 2% ammonium bicarbonate, 11% triethyl citrate, and 20% talc. The solvent of the spray or feed solution is purified water. After the coating step, the mass of the pellets has increased by 25% to 40% (preferably 35%) and the drug (compound 1) concentration in the granules / pellets / beads is about 98 mg / g (i.e., 9.8%). The particles obtained in this embodiment have an average diameter of about 0.9 mm. A quantitative summary of the enteric layered drug granules / pellets / beads is given below:

[0230] [Table 3]

[0231] Surprisingly, the release profile of Compound 1 layered pellets coated with HPMCAS has been shown to be very robust not only against potential weight gain variations due to coating, but also against potential pH variations that may be present in the intestine. Within the pH range of pH 6.0 to 6.8, the embodiments release drug consistently with highly reproducible kinetics. After a lag time or delay of 5 to 10 minutes, drug release from the granules / pellets / beads is fast and reaches a plateau after another 10 minutes. Thus, 100% of Compound 1 should be available for local action upon entering the ileum.

[0232] 1.2.2 Preparation of Eudragit® L100 / S100 coated granules / pellets / beads The drug-layered pellets are coated with a coating solution, or feed solution, consisting of solute and solvent, in a preferred ratio of 15% w / w solute to 85% w / w solvent. The solute includes a four-component mixture of Eudragit® L100 and Eudragit® S100 used as enteric polymers, triethyl citrate used as plasticizer, and talc used as flow agent / lubricant, in a preferred ratio of 63% Eudragit® L100, 11% Eudragit® S100, 7% triethyl citrate, and 19% talc. The solvent of the spray solution or feed solution is a two-component mixture of isopropyl alcohol and purified water in a ratio of 92% w / w (isopropyl alcohol) to 8% w / w (purified water). After the coating step, the mass of the pellets has increased by 45% (weight gain) and the drug concentration of the granules / pellets / beads is about 91 mg / g (i.e., 9.1%). The resulting particles in embodiments have an average diameter in the range of about 0.9. A quantitative summary of the enteric coated layered drug granules / pellets / beads is provided below.

[0233] [Table 4]

[0234] The use of Eudragit® L100 and Eudragit® S100 allows the particles to deliver Compound 1 to the lower part of the gastrointestinal tract. Depending on the weight gain, the lag time, or delay, can be increased from 15 to 30 minutes. This allows the granules / pellets / beads to begin drug release in the jejunum and complete release in the ileum. The preferred weight gain to adjust the required lag time is in the range of 35% to 55%.

[0235] The enteric coated layered drug granules / pellets / beads can be provided in different dosage strengths by encapsulating the required amount of pellets in hard capsules or by filling the required amount of pellets in sachets or stick packs. These products are delayed release dosage forms.

[0236] 2. Preparation method 2

[0237] 2.1 Preparation of mini-tablets Compound 1 is formulated into coated mini-tablets. The coating options are the same as those described for spherical multiparticulates, but the manufacture of mini-tablets applies various operations, such as mixing, granulation, and compression. In a preferred embodiment, (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 pharma- ceutically acceptable salt, low-substituted hydroxypropylcellulose used as binder, croscarmellose sodium used as disintegrant, and mannitol used as filler are sieved and premixed in a suitable granulator. The powder blend is wet-granulated by slowly adding a solution of hydroxypropylcellulose in ethanol 96%. The wet granules are then mixed until the desired granule structure is reached. The wet granules are then wet-sieved and subsequently dried at 70°C ± 5°C until the required loss on drying is reached. The dried granules are sieved and mixed with sieved adipic acid and silicon dioxide. After the addition of talc, the final blend is compressed into mini tablets using a multi-tip mini tablet punch. The resulting tablet weight is about 13 mg. The qualitative and quantitative composition in the embodiment is shown below:

[0238] [Table 5]

[0239] 2.2 Preparation of enteric polymer-coated mini-tablets As described for granules / pellets / beads, the mini-tablets can also be coated with HPMCAS-HF or a mixture of Eudragit® L100 and Eudragit® S100 to achieve the desired delayed release profile. The qualitative and quantitative composition of the film-coated mini-tablets is given below: a) HPMCAS

[0240] [Table 6]

[0241] b) Eudragit® L100 and Eudragit® S100

[0242] [Table 7]

[0243] Mini-tablets can also be obtained by hot melt extrusion. In a preferred embodiment, (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 pharma- ceutically acceptable salt, is mixed with copovidone (a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a mass ratio of 6:4) and melted in a hot melt extruder. The melt is cooled to room temperature and ground using a hammer mill. The ground extrudate is mixed with croscarmellose sodium, silicon dioxide, and finally magnesium stearate. The final blend is compressed into mini-tablets using a multi-tip tablet punch.

[0244] The following examples are prepared by using any of the methods described above.

[0245] [Example 1] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release granules provided in stick packs based on pellets as core material and HPMCAS as enteric polymer

[0246] [Table 8]

[0247] [Example 2] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release granules presented in stick packs based on pellets as core material and HPMCAS as enteric polymer and sodium dodecyl sulfate as surfactant

[0248] [Table 9]

[0249] [Example 3] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release granules presented in stick packs based on pellets as core material and hypromellose (HPMC) as sustained release polymer and HPMCAS as enteric polymer

[0250] [Table 10]

[0251] [Example 4] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release granules provided in stick packs based on pellets as core material and methacrylic acid-methyl methacrylate copolymer as enteric polymer

[0252] [Table 11]

[0253] [Example 5] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release granules provided in stick packs based on pellets as core material and methacrylic acid-methyl methacrylate copolymer as enteric polymer and ethylcellulose as sustained release polymer.

[0254] [Table 12]

[0255] [Example 6] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release mini-tablets provided in stick packs based on mini-tablets as core material and HPMCAS as enteric polymer

[0256] [Table 13]

[0257] [Example 7] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release mini-tablets presented in stick packs based on mini-tablets as core material and HPMCAS as enteric polymer

[0258] [Table 14]

[0259] [Example 8] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release mini-tablets presented in stick packs based on mini-tablets as core material and methacrylic acid-methyl methacrylate copolymer as enteric polymer

[0260] [Table 15]

[0261] [Example 9] Qualitative and quantitative composition of Compound 1 (50 mg) delayed release mini-tablets presented in stick packs based on mini-tablets as core material and methacrylic acid-methyl methacrylate copolymer as enteric polymer

[0262] [Table 16]

[0263] [Example 10] In vitro dissolution profile of Compound 1 (50 mg) delayed release granules The oral formulations of the present invention can be evaluated in vitro by dissolution testing methods under conditions reflecting the physicochemical properties of compound 1 and oral solid formulations, taking into account the required delayed release. Based on these properties, and taking into account the requirements of the European and US Pharmacopoeias, a two-stage full change dissolution method using a paddle apparatus (i.e., Apparatus II) operating at a stirring speed of 100 rpm has been developed. The gastric resistance of the oral solid dosage form can be verified in 500 mL of simulated gastric fluid (0.1 N HCl, pH 1.2) for 2 hours. Drug release can be tested after transferring the dosage form to 900 mL of simulated intestinal fluid (50 mM phosphate buffer adjusted to either pH value 6.2, 6.5 or 6.8) containing 0.5% sodium dodecyl sulfate as a surfactant. Dissolution tests are performed under sink conditions at 37° C. to reflect in vivo conditions. The amount of compound 1 released in the dissolution medium can be quantified using an HPLC / UV method with a detection wavelength of 316 nm (FIG. 1).

[0264] ·Equipment: USP Equipment II Stirring speed: 100 rpm ·Dissolution medium: - Acidic stage: Medium: 0.1N HCl, pH 1.2 Capacity: 500mL - Buffer stage: Medium: 50 mM phosphate buffer pH 6.8 containing 0.5% sodium dodecyl sulfate Capacity: 900mL Sample batch number: 209702CW19 Drug layered granules with 35% HPCMAS-HF, 209702CW017_3 Drug layered granules with 35% Eudragit® L100 / S100 Analytical procedure: HPLC / UV Dissolution profile

Claims

1. 1. An oral formulation adapted for selective delivery of a drug to the small intestine of a mammal, comprising or consisting of: A plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, each particle 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-carboxamido)-7-oxohept-2-enoate of formula (I): 【Chemistry 1】 or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, a core material, and an enteric coating polymer; Here, each particle is coated with at least one coating layer comprising or consisting of said enteric coating polymer.

2. 10. The oral formulation of claim 1, wherein the enteric coating polymer comprises or is selected from the group consisting of methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate, hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, shellac, and mixtures of two or more of the enteric coating polymers.

3. the hypromellose acetate succinate is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof; and / or 3. The oral formulation of claim 2, wherein the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of Eudragit® L100, Eudragit® S100, and mixtures thereof.

4. 4. The oral formulation of claim 1, wherein each particle further comprises one or more binders, buffers, colorants, plasticizers, flow agents, disintegrants, pH adjusters, surfactants, and / or fillers.

5. 4. The oral dosage form of any one of claims 1 to 3, wherein the enteric coating polymer is included in or forms the outer layer of the coating surrounding the core material.

6. When the particles are in the form of coated minitablets, the core material comprises one or more binders, disintegrants, flow agents, pH adjusters, and / or fillers. The oral formulation according to any one of claims 1 to 4.

7. 7. The oral formulation of claim 6, wherein the binder is selected from the group consisting of sugars, sucrose, polysaccharides, xanthan gum, guar gum, carrageenan, starches derived from wheat, corn, rice and potato, pre-aggregated starches derived from wheat, corn, rice and potato, sodium starch glycolate, natural gums, acacia gum, gelatin, tragacanth, seaweed derivatives, alginic acid, sodium alginate, ammonium calcium alginate, cellulose, cellulose derivatives, hydroxypropyl cellulose, L-hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and mixtures thereof.

8. the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, or a mixture thereof; The disintegrant is croscarmellose sodium, the glidant is talc, silicon dioxide, or a mixture thereof; the pH adjuster is adipic acid, and / or 7. The oral formulation of claim 6, wherein the filler is mannitol.

9. 10. The oral formulation of claim 1, wherein at least one coating layer further comprises at least one buffering agent, plasticizer, and / or glidant.

10. the buffer is ammonium bicarbonate; the plasticizer is triethyl citrate, and / or 10. The oral formulation of claim 9, wherein the glidant is talc, silicon dioxide, or a mixture thereof.

11. 7. The oral formulation of claim 6, Each particle in the form of a coated mini-tablet is an oral formulation comprising: 5 wt % to 15 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, its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt, and 50 wt % to 90 wt % of a core material comprising or consisting of said binder, said disintegrant, said fluidizing agent, said pH adjuster and / or said filler; and 1 wt % to 10 wt % of the enteric coating polymer.

12. 5. The oral formulation of claim 4, wherein each particle comprises or consists of: 5 wt % to 15 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, 1 wt % to 10 wt % HPMCAS-HF, 15 wt % to 30 wt % low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 15 wt% to 30 wt% croscarmellose sodium, 15 wt% to 30 wt% mannitol, 0.1 wt % to 3.0 wt % triethyl citrate; 0 wt % to 1.0 wt % ammonium bicarbonate, 3 wt % to 10 wt % of talc, silicon dioxide, or a mixture thereof, and optionally 5.0 wt % to 10.0 wt % adipic acid; or 5 wt % to 15 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, 1 wt % to 10 wt % Eudragit® L100 / S100, 15 wt % to 30 wt % low-substituted hydroxypropyl cellulose, 1 wt % to 10% hydroxypropyl cellulose, 15 wt% to 30 wt% croscarmellose sodium, 15 wt% to 30 wt% mannitol, 0.1 wt % to 3.0 wt % triethyl citrate; 3 wt % to 10 wt % of talc, silicon dioxide, or a mixture thereof, and Optionally, 5.0 wt % to 10.0 wt % adipic acid.

13. 5. The oral formulation of claim 4, wherein each particle comprises: 8 wt % to 12 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, 3 wt% to 6 wt% HPMCAS-HF; 20 wt % to 26 wt % low-substituted hydroxypropyl cellulose; 2 wt % to 4 wt % hydroxypropyl cellulose, 20 wt% to 26 wt% croscarmellose sodium 20 wt% to 26 wt% mannitol, 0.1 wt % to 1.0 wt % triethyl citrate; 0.01 wt % to 0.5 wt % ammonium bicarbonate, 4 wt % to 8 wt % talc, 0.5 wt % to 1.5 wt % silicon dioxide, and Optionally, 6 wt % to 10 wt % adipic acid or Each particle is an oral formulation consisting of: 8 wt % to 12 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, 3 wt % to 6 wt % Eudragit® L100, 0.1 wt % to 1.5 wt % Eudragit® S100, 20 wt % to 26 wt % low-substituted hydroxypropyl cellulose; 2 wt % to 4 wt % hydroxypropyl cellulose, 20 wt% to 26 wt% croscarmellose sodium 20 wt% to 26 wt% mannitol, 0.1 wt % to 1.0 wt % triethyl citrate; 4 wt % to 8 wt % talc, and 0.5 wt % to 1.5 wt % silicon dioxide, and Optionally, 6 wt % to 10 wt % adipic acid.

14. 10. The oral formulation of claim 1, wherein when the particles are in the form of coated granules, coated pellets, coated beads, or coated minicapsules, the core material is in the form of a core pellet and consists of tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose.

15. 15. The oral formulation of claim 14, wherein the core pellets are coated with (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, an enantiomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof, together with at least one binder, colorant, flow agent, surfactant, and / or filler.

16. 15. The oral formulation of claim 14, wherein the core pellet size ranges from 100 μm to 14000 μm.

17. 17. The oral formulation of any one of claims 14 to 16, wherein the core pellet consists of microcrystalline cellulose and the size of the core pellet ranges from 100 μm to 355 μm.

18. the binder is polyvinylpyrrolidone; the surfactant is sodium dodecyl sulfate, and / or 17. The oral formulation of claim 15 or claim 16, wherein the filler is lactose monohydrate.

19. The oral formulation according to any one of claims 14 to 16, wherein the coating layer comprising the enteric coating polymer further comprises at least one buffering agent, plasticizer, and / or fluidizing agent.

20. the buffer is ammonium bicarbonate; the plasticizer is triethyl citrate, and / or 20. The oral formulation of claim 19, wherein the fluidizing agent is talc.

21. the binder is povidone K25; the colorant is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the filler is lactose monohydrate; the buffer is ammonium bicarbonate; the plasticizer is triethyl citrate, and / or The oral formulation according to any one of claims 14 to 16, wherein the fluidizing agent is talc.

22. The oral formulation according to any one of claims 14 to 16, wherein each particle is further coated with a coating layer comprising or consisting of a sustained release polymer.

23. 23. The oral formulation of claim 22, wherein the sustained release polymer is selected from hypromellose, ethylcellulose, Eudragit® RL100, Eudragit® RS100, and mixtures thereof.

24. 17. The oral formulation according to any one of claims 14 to 16, wherein each particle comprises: 5 wt % to 15 wt % of (S,E)-methyl-7-(1-(2-(2-ethoxy)methyl)-2-methyl ... (1-methyl-1H-imidazole-5-carboxamido)-7-oxohept-2-enoate, or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof; 30 wt% to 55 wt% of a core material, and 15 wt% to 30 wt% of the enteric coating polymer.

25. 17. The oral formulation according to any one of claims 14 to 16, wherein each particle comprises: 5 wt % to 15 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 of formula (I), or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, and 30 wt% to 55 wt% of the core material; 15 wt % to 30 wt % of an enteric coating polymer, and 0.1 wt% to 2.0 wt% of a sustained release polymer.

26. 17. The oral formulation according to any one of claims 14 to 16, wherein each particle comprises: 5 wt % to 15 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, 30 wt% to 45 wt% of a microcrystalline cellulose core; 15 wt% to 25 wt% HPMCAS-HF, 10 wt% to 20 wt% lactose monohydrate, 10 wt % to 15 wt % talc, 1.0 wt % to 3.0 wt % triethyl citrate; 0.1 wt % to 1.0 wt % ammonium bicarbonate, and optionally, 0.1 wt % to 2.0 wt % sodium dodecyl sulfate, and / or 0.1 wt % to 2.0 wt % HPMC, or 5 wt % to 15 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, 30 wt% to 45 wt% microcrystalline cellulose core 15 wt% to 30 wt% Eudragit® L100 and 0 wt% to 5 wt% Eudragit® S100; 10 wt% to 20 wt% lactose monohydrate, 10 wt % to 15 wt % talc, 1.0 wt % to 3.0 wt % triethyl citrate, and / or Optionally, 0.1 wt% to 2.0 wt% ethylcellulose and PEG.

27. 17. The oral formulation according to any one of claims 14 to 16, wherein each particle comprises: 7 wt % to 12 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, 37 wt% to 41 wt% of a microcrystalline cellulose core; 15 wt% to 19 wt% HPMCAS-HF; 14 wt% to 18 wt% lactose monohydrate, 11 wt % to 15 wt % talc, 0.5 wt% to 2.0 wt% povidone K25, 1.0 wt % to 3.0 wt % triethyl citrate, and 0.1 wt % to 1.0 wt % ammonium bicarbonate, or The particles are an oral formulation comprising: 7 wt % to 12 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, 37 wt% to 41 wt% of a microcrystalline cellulose core; 15 wt% to 19 wt% HPMCAS-HF; 12 wt% to 16 wt% lactose monohydrate, 11 wt % to 15 wt % talc, 0.5 wt% to 2.0 wt% povidone K25, 1.0 wt% to 3.0 wt% triethyl citrate 0.5 wt % to 2.0 wt % sodium dodecyl sulfate, and 0.1 wt % to 1.0 wt % ammonium bicarbonate, or The particles are an oral formulation comprising: 7 wt % to 12 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, 37 wt% to 41 wt% of a microcrystalline cellulose core; 15 wt% to 19 wt% HPMCAS-HF; 13 wt% to 17 wt% lactose monohydrate, 11 wt % to 15 wt % talc, 0.5 wt% to 2.0 wt% povidone K25, 1.0 wt % to 3.0 wt % of triethyl citrate: 0.1 wt % to 1.0 wt % ammonium bicarbonate, and 0.5 wt % to 2.0 wt % HPMC; or The particles are an oral formulation comprising: 7 wt % to 12 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, 33 wt% to 37 wt% of a microcrystalline cellulose core; 20 wt% to 24 wt% Eudragit® L100 and 3 wt% to 5 wt% Eudragit® S100; 12 wt% to 16 wt% lactose monohydrate, 12 wt % to 15 wt % talc, and 1.0 wt % to 3.0 wt % triethyl citrate; or The particles are an oral formulation comprising: 7 wt % to 12 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, 35 wt% to 39 wt% of a microcrystalline cellulose core; 23 wt% to 27 wt% Eudragit® L100, 10 wt% to 14 wt% lactose monohydrate, 12 wt % to 15 wt % talc, 1.0 wt % to 3.0 wt % triethyl citrate; 0.01 wt % to 0.5 wt % ethyl cellulose, and 0.01 wt% to 0.5 wt% Macrogol® 6000.

28. The oral formulation according to any one of claims 1 to 3 and claims 14 to 16, wherein the enteric coating polymer is soluble at a pH value in the range of 5.5 to 6.

8.

29. 17. The oral formulation of any one of claims 14 to 16, wherein the size of each particle ranges from 0.5 mm to 1.3 mm.

30. 10. The oral formulation of claim 1, wherein the plurality of particles is contained in a capsule, sachet, or stick pack, or formed as a tablet.

31. 10. The oral formulation of claim 1 for use in the prevention and / or treatment of intestinal fibrosis.

32. 32. The oral formulation for use of claim 31, wherein the oral formulation is adapted to release (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, its enantiomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, starting in the jejunum and completing in the ileum.

33. 33. The oral formulation for use according to claim 31 or claim 32, wherein the intestinal fibrosis is fibrostenosing Crohn's disease.

34. 10. A method for preparing the oral formulation of claim 1, comprising the steps of: Step A) preparing a plurality of particles in the form of coated granules, coated pellets, coated beads, coated minicapsules, or coated minitablets, wherein each particle comprises: (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 of formula (I) 【Chemistry 2】 or an enantiomer, solvate, hydrate or pharmaceutically acceptable salt thereof, and Core material, Step B) Coating each particle with at least one coating solution comprising an enteric coating polymer.

35. 35. The method of claim 34, further comprising the steps of: Step C) Coating each particle with a coating solution containing a sustained release polymer.

36. 35. The method of claim 34, wherein when the particles are in the form of coated minitablets, the core material comprises one or more binders, disintegrants, flow agents, pH adjusters, and / or fillers.

37. the binder is low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose, povidone K25, or a mixture thereof; The disintegrant is croscarmellose sodium, The fluidizing agent is talc, the pH adjuster is adipic acid, and / or 37. The method of claim 36, wherein the filler is mannitol, lactose monohydrate, or a mixture thereof.

38. 35. The method of claim 34, wherein the core material is in the form of a core pellet and consists of tartaric acid, lactose, sugar, corn starch, starch hydroxylate, silica, or microcrystalline cellulose, and the core pellet is coated with (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, an enantiomer, solvate, hydrate, or a pharmaceutically acceptable salt thereof, together with at least one binder, colorant, flow agent, surfactant, and / or filler.

39. the binder is povidone K25; the coloring agent is selected from titanium dioxide, iron (III) oxide, iron (II, III) oxide, hydrated ferric oxide, lactose monohydrate, carnauba wax, and mixtures thereof; the surfactant is sodium dodecyl sulfate, the glidant is talc, and / or 39. The method of claim 38, wherein the filler is lactose monohydrate.

40. In step B), The method of any one of claims 34 to 39, wherein the at least one coating solution further comprises at least one buffering agent, plasticizer, and / or flow agent.

41. the buffer is ammonium bicarbonate; the plasticizer is triethyl citrate, and / or 41. The method of claim 40, wherein the glidant is talc, silicon dioxide, and mixtures thereof.

42. 40. The method of any one of claims 34 to 39, wherein in step B) the enteric coating polymer is selected from the group consisting of methacrylic acid-methyl methacrylate copolymer, acrylic acid-methyl methacrylate copolymer, methacrylic acid-methyl acrylate copolymer, methacrylic acid-ethyl acrylate copolymer, acrylic acid-methyl acrylate copolymer, methyl acrylate-methyl methacrylate-methacrylic acid copolymer, hypromellose acetate succinate (HPMCAS), hypromellose phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate (CAP), shellac, and mixtures of two or more of the enteric coating polymers.

43. the hypromellose acetate succinate is selected from the group consisting of hypromellose acetate succinate HPMCAS-LF, HPMCAS-MF, HPMCAS-HF, HPMCAS-LMP, HPMCAS-MMP, HPMCAS-HMP, HPMCAS-LG, HPMCAS-MG, HPMCAS-HG, and mixtures thereof; and / or the methacrylic acid-methyl methacrylate copolymer is selected from the group consisting of Eudragit® L100, Eudragit® S100, and mixtures thereof; 43. The method of claim 42.

44. The method according to any one of claims 34 to 39, wherein in step B) water or a mixture of water and isopropyl alcohol is used for preparing the at least one coating solution.

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