Pharmaceutical composition for the treatment of inflammatory bowel disease.

Description

/ 27 Pharmaceutical Composition for the Treatment of Inflammatory Bowel Disease - Technical Field

[001] This disclosure relates to a pharmaceutical composition useful as a therapeutic agent for inflammatory bowel disease. BACKGROUND

[002] Inflammatory bowel disease (IBD) refers to diseases that cause inflammation in the intestines, primarily represented by ulcerative colitis (UC) and Crohn's disease (CD). The cause is unknown and there is still no cure, but the basic philosophy of treatment is to administer remission induction therapy during the active phase and continue remission maintenance therapy after remission induction (Riichi Hisamatsu, Diagnostic criteria and treatment guidelines for ulcerative colitis and Crohn's disease (revised edition for 2021)).

[003] Conventional treatment has focused on 5-aminosalicylic acid preparations (sometimes called 5-ASA preparations) and corticosteroids, but in recent years, α4β7 anti-integrin antibody preparations have been used.

[004] On the other hand, the development of low molecular weight compounds administerable orally has also progressed, and compounds of the following formula (I) have been reported (International Publication No. WO2017 / 135472).

[005] In formula (I), R represents a hydroxyl group or a group Petition 870250090468, dated 03 / 10 / 2025, p. 13 / 52 2 / 27 isobutyloxy.

[006] When R is an isobutyloxy group, it is the ester shown in the following formula (1) (sometimes referred to as Compound (1) in the present specification), and when R is a hydroxyl group, it is the carboxylic acid shown in the following formula (2) (sometimes referred to as Compound (2) in the present specification). The ester of formula (1) is assumed to be absorbed as a prodrug and converted into the active metabolite of formula (2) in vivo. SUMMARY OF THE INVENTION

[007] As described above, several therapeutic agents for inflammatory bowel disease have been developed, but 5ASA and corticosteroid preparations may be insufficiently effective, and antibody preparations have disadvantages such as complex pharmacokinetics, limited methods of administration, high production costs, and secondary ineffectiveness due to the induction of antidrug antibodies attributable to proteins. Petition 870250090468, dated 03 / 10 / 2025, page 14 / 52 / 27 of high molecular weight. On the other hand, low molecular weight compounds can overcome the disadvantages of antibody preparations, but even with low molecular weight compounds, it has been difficult to predict the effective dosage in the treatment of inflammatory bowel disease based solely on chemical structure and similarities, due to interactions with a wide variety of substances in vivo and complex pharmacokinetics.

[008] As a result of diligent studies to solve the above problems, the inventors discovered that a compound represented by formula (I) or a pharmaceutically acceptable salt thereof acts effectively on inflammatory bowel disease at a given dosage.

[009] In other words, this disclosure may have the following configurations: [1] A pharmaceutical composition for the treatment of inflammatory bowel disease, comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 50 mg or more per day as an active ingredient, (I) where R represents a hydroxyl group or an isobutyloxy group.

[0010] [2] The pharmaceutical composition according to [1], in which the compound or a pharmaceutically acceptable salt thereof is administered to Petition 870250090468, dated 03 / 10 / 2025, page 15 / 52 4 / 27 a human being at a dose of 100 mg or more per day as an active ingredient.

[0011] [3] The pharmaceutical composition according to [1], wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 200 mg or more per day as an active ingredient.

[0012] [4] The pharmaceutical composition according to any of [1] to [3], which is an oral dosage form.

[0013] [5] The pharmaceutical composition according to any of [1] to [4], in which the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more.

[0014] [6] The pharmaceutical composition according to any of [1] to [5], in which the compound or a pharmaceutically acceptable salt thereof is administered 1 to 5 times a day.

[0015] [7] The pharmaceutical composition according to any of [1] to [6], which is in the form of a self-emulsifying preparation.

[0016] [8] The pharmaceutical composition according to any of [1] to [7], wherein the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more, such that a plasma concentration as a minimum value of the compound represented by the following formula (2) is 1.9 ng / mL or more.

[0017] [9] The pharmaceutical composition according to any of Petition 870250090468, dated 03 / 10 / 2025, p. 16 / 52 / 27 [1] to [7], wherein the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more, such that a plasma concentration as a minimum value of the compound represented by formula (2) above is 6.9 ng / mL or more.

[0018]

[10] The pharmaceutical composition according to any one of [1] to [9], wherein the inflammatory bowel disease is ulcerative colitis.

[0019]

[11] The pharmaceutical composition according to any one of [1] to

[10] , wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 800 mg or less per day as an active ingredient.

[0020] [A]

[0021] A method of treating inflammatory bowel disease comprising administering a therapeutically effective amount of a compound represented by formula (I) as defined in [1] above or a pharmaceutically acceptable salt thereof to a patient requiring treatment.

[0022] [B]

[0023] The compound represented by formula (I) as defined in [1] above or a pharmaceutically acceptable salt thereof for use in the treatment of inflammatory bowel disease.

[0024] [C]

[0025] Use of the compound represented by formula (I) as defined in [1] above or a pharmaceutically acceptable salt thereof in the treatment of inflammatory bowel disease.

[0026] [D]

[0027] Use of the compound represented by formula (I) as defined in [1] above or a pharmaceutically acceptable salt thereof in the production of a medicament for the treatment of inflammatory bowel disease. Petition 870250090468, dated 03 / 10 / 2025, page 17 / 52 / 27

[0028] By using the pharmaceutical composition of this disclosure, inflammatory bowel disease can be treated effectively. BRIEF DESCRIPTION OF THE FIGURES

[0029] Fig. 1A is a diagram showing the plasma concentration profile of Compound (2) after single dose administration.

[0030] Fig. 1B is a diagram showing the plasma concentration profile of Compound (2) after single dose administration.

[0031] Fig. 2A is a diagram showing the 24-hour minimum value profile after dosing of Compound (2) following repeated administration.

[0032] Fig. 2B is a diagram showing the 12-hour minimum value profile after dosing of Compound (2) following repeated administration.

[0033] Fig. 3A is a diagram showing the plasma concentration profile of Compound (2) after repeated administration (L-SEDDS 400 mg once daily) on day 10 and after single dose administration.

[0034] Fig. 3B is a diagram showing the plasma concentration profile of Compound (2) after repeated administration (C-SEDDS 200 mg twice daily) on day 10 and after single dose administration.

[0035] Fig. 4 is a diagram showing the predicted plasma concentration profile of Compound (2) on day 10 of repeated administration.

[0036] Fig. 5 is a diagram showing the concentration of Compound (2) in the collected plasma and the inhibitory activity of ligand binding.

[0037] Fig. 6 is a diagram showing the predicted plasma concentration profile of Compound (2) on day 10 of twice-daily repeated administration. DESCRIPTION OF THE MODALITIES

[0038] The pharmaceutical composition of this disclosure contains, as an active ingredient, a compound represented by the following formula (I) (hereinafter sometimes simply referred to as Compound (I)) or a salt Petition 870250090468, dated 03 / 10 / 2025, page 18 / 52 / 27 pharmaceutically acceptable thereof. Compound (I) or a pharmaceutically acceptable salt thereof may act extremely effectively in patients with inflammatory bowel disease.

[0039] Compound (I) can be produced, for example, by the method described in International Publication No. WO2017 / 135472 (Compound A45, Compound P97).

[0040] In the present disclosure, the term pharmaceutically acceptable salt is not particularly limited, provided that Compound (I) can form a salt and still retain pharmacological activity. For example, for acidic groups, such as the carboxyl group in formula (I), examples include ammonium salts; alkali metal salts, such as sodium and potassium; alkaline earth metal salts, such as calcium and magnesium; aluminum salts; zinc salts; salts with organic amines, such as triethylamine, ethanolamine, morpholine, piperidine, and dicyclohexylamine; and salts with basic amino acids, such as arginine and lysine. For basic groups in formula (I), examples include salts with inorganic acids, such as hydrochloric acid, sulfuric acid, and phosphoric acid; salts with organic carboxylic acids, such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, and succinic acid; and salts containing organic sulfonic acids, such as methanesulfonic acid and p-toluenesulfonic acid.This also applies to the pharmaceutically acceptable salts of Compound (1) and Compound (2).

[0041] As a method for forming the above salts, known methods may be appropriately used. For example, a method of mixing Compound (I) and a required acid or base in a suitable proportion in a solvent or dispersant may be mentioned, or a method of subjecting Compound (I) in the form of another salt to cation or anion exchange.

[0042] In addition, Compound (I) also includes its solvates, such as hydrates and alcohol adducts.

[0043] The pharmaceutical composition of this disclosure is useful for Petition 870250090468, dated 03 / 10 / 2025, page 19 / 52 / 27, regarding the treatment of inflammatory bowel disease. Treatment in this specification includes preventing recurrence of inflammatory bowel disease, suppressing progression of inflammatory bowel disease, relieving symptoms of inflammatory bowel disease, maintaining remission of inflammatory bowel disease, and curing inflammatory bowel disease.

[0044] Examples of inflammatory bowel disease include ulcerative colitis and Crohn's disease.

[0045] The inflammatory bowel disease for which the pharmaceutical composition of the present disclosure is particularly useful is, for example, inflammatory bowel disease in which an α4 integrin-dependent adhesion process is involved in the pathology.

[0046] In addition, the inflammatory bowel disease for which the pharmaceutical composition of the present disclosure is particularly useful is, for example, ulcerative colitis. <Dose por Dia>

[0047] Compound (I) or a pharmaceutically acceptable salt thereof is administered to the target human at a dose of 50 mg or more per day as the active ingredient, preferably at a dose of 100 mg or more per day as the active ingredient, more preferably at a dose of 200 mg or more per day, even more preferably at a dose of 300 mg or more per day, and even more preferably at a dose of 400 mg or more per day. The upper limit is not particularly restricted, but is preferably 1000 mg or less per day, and more preferably 800 mg or less per day.

[0048] Among these, Compound (I) or a pharmaceutically acceptable salt thereof is particularly preferably administered to the target human at a dose of 100 to 800 mg, 200 to 800 mg, 300 to 800 mg or 400 to 800 mg per day, and most preferably at a dose of 400 mg per day. Petition 870250090468, dated 03 / 10 / 2025, p. 20 / 52 / 27<Número de Doses por Dia>

[0049] There is no specific restriction as to the number of doses per day. For example, Compound (I) or a pharmaceutically acceptable salt thereof may be administered to the target human from 1 to 5 times a day. Among these, it is preferably administered 1 to 4 times a day, more preferably 1 to 3 times a day, and most preferably once or twice a day.

[0050] In addition, when administering multiple times a day, the dose per administration is preferably an amount obtained by dividing the daily dose mentioned above by the number of doses per day.

[0051] Among these, Compound (1) or a pharmaceutically acceptable salt thereof is preferably administered to the target human once or twice daily at a dose of 100 mg or more per administration, more preferably once or twice daily at a dose of 100 to 800 mg per administration, even more preferably once or twice daily at a dose of 200 to 400 mg per administration, and most preferably once or twice daily at a dose of 400 mg per administration or twice daily at a dose of 200 mg per administration.

[0052] As another embodiment, Compound (I) or a pharmaceutically acceptable salt thereof is preferably administered to the target human twice daily at a dose of 50 mg or more per administration, more preferably twice daily at a dose of 50 to 400 mg per administration, and even more preferably twice daily at a dose of 100 to 200 mg per administration. <Período de Administração>

[0053] The administration period is not particularly limited and, for example, it can be administered until the symptoms of inflammatory bowel disease in the target human improve. The compound (1) or a Petition 870250090468, dated 03 / 10 / 2025, page 21 / 52 / 27 a pharmaceutically acceptable salt thereof is preferably administered continuously for 2 days or more, more preferably administered continuously for 7 days or more, and even more preferably administered continuously for 10 days or more. Among these, it is preferable to administer Compound (I) or a pharmaceutically acceptable salt thereof for at least 4 weeks, more preferably for at least 8 weeks, and even more preferably for at least 1 year. <Administração Alvo>

[0054] In this disclosure, the preferred human target is a patient with inflammatory bowel disease, and the most preferred target is a patient with ulcerative colitis. <Forma de Dosagem>

[0055] The pharmaceutical composition of the present disclosure may be in the form of an oral preparation, intravenous injection, enema preparation, suppository, etc., but is preferably in the form of an oral preparation. Examples of oral preparations include tablets, powders, pills, granules, capsules, solutions, sugar-coated tablets, depot preparations and syrups, each of which may be produced according to conventional methods using general pharmaceutical excipients.

[0056] For example, tablets can be obtained by mixing Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with known excipients, for example, inert diluents such as lactose, calcium carbonate or calcium phosphate; binders such as gum arabic, corn starch or gelatin; disintegrants such as alginic acid, corn starch, dextrin, pullulan, corn starch, potato starch or pregelatinized starch; sweeteners such as sucrose, lactose or saccharin; flavoring agents such as peppermint, wintergreen or cherry oil; glidants such as magnesium stearate, talc, magnesium oxide, magnesium lauryl sulfate, magnesium aluminometasilicate or Petition 870250090468, dated 03 / 10 / 2025, page 22 / 52 / 27 carboxymethylcellulose; surfactants such as sodium lauryl sulfate, polysorbate 80, sucrose fatty acid esters, polyoxyl 40 stearate, polyoxyl 35 castor oil, polyoxyethylene 60 hydrogenated castor oil, sorbitan monostearate, sorbitan monopalmitate and PEG-8 glyceryl caprylate; excipients such as sucrose, glucose, reduced maltose, mannitol, sorbitol, xylitol and trehalose; excipients for soft gelatin capsules and suppositories such as fats, waxes, semi-solid and liquid polyols, natural oils and hydrogenated oils; and excipients for solutions such as water, alcohol, glycerol, polyols, sucrose, invert sugar, glucose and vegetable oils.

[0057] For example, examples of capsule preparations include those in which the pharmaceutical composition of the present disclosure is contained in hard capsules, soft capsules, etc. Hard capsule preparations are those in which a powdered or granular pharmaceutical composition is placed in a capsule produced using gelatin or similar as a base, and soft capsules are those in which a base obtained by adding glycerin or sorbitol to gelatin is used primarily to enclose a liquid pharmaceutical composition and mold it into a capsule shape. There are various shapes, such as spherical and oval, and various sizes.

[0058] In addition, the pharmaceutical composition of the present disclosure may be in the form of a self-emulsifying preparation, such as SEDDS, SMEDDS and SNEDDS. Examples of such self-emulsifying preparations include, but are not limited to, liquid self-emulsifying drug delivery systems (L-SEDDS) and soft capsule self-emulsifying drug delivery systems (CSEDDS).

[0059] The self-emulsifying preparation is not particularly limited, provided it can dissolve or disperse Compound (I) or a pharmaceutically acceptable salt thereof, and various surfactants and the like are used. Examples of such surfactants include lipophilic surfactants (for Petition 870250090468, dated 03 / 10 / 2025, page 23 / 52 / 27 example, polyglyceryl-2 dioleate, polyglyceryl-3 dioleate, polyglyceryl-10 trioleate, propylene glycol monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl dilaurate, glyceryl monolinoleate, etc.) and hydrophilic surfactants (e.g., castor oil polyoxyl 40, castor oil polyoxyl 35, PEG-25 trioleate, PEG-60 corn glycerides, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-50 castor oil, PEG-50 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-8 glyceryl caprylate / caprate, lauroyl polyoxyl-32 glycerides, linoleyl polyoxyl-6 glycerides, oleoyl polyoxyl-6 glycerides, stearoyl polyoxyl-32 glycerides, PEG-6 glyceryl caprylate / caprate, polyglyceryl-10 monooleate, polyglyceryl-10 laurate, polyglyceryl-15 Hydroxystearate, α-tocopheryl PEG 400 succinate, α-tocopheryl PEG 1000 succinate, dl-α-tocopheryl PEG 1000 succinate, da-tocopheryl PEG 1000 succinate, etc.). In addition to the surfactants mentioned above, a co-solvent (e.g., acetic acid, sorbitol, mannitol, glycerol, triacetin, triethyl citrate, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, propylene carbonate, ethanol, propylene glycol, etc.).) can be added.

[0060] These surfactants can be used alone or in combination. <Concentração Plasmática>

[0061] The pharmaceutical composition of the present disclosure is administered to humans at a dose that provides a therapeutically effective improvement in inflammatory bowel disease. The effect depends on the maximum plasma concentration (Cmax) of Compound (2) and the steady-state plasma concentration (minimum value) 6 hours, 8 hours, 12 hours or 24 hours later.

[0062] For example, the pharmaceutical composition of the present disclosure is preferably administered in such a way that the Cmax of Compound (2) is, after single or repeated dose administration, 1.9 ng / mL Petition 870250090468, dated 03 / 10 / 2025, page. 24 / 52 / 27 or more, 2.0 ng / mL or more, 2.5 ng / mL or more, 3.0 ng / mL or more, 3.5 ng / mL or more, 4.0 ng / mL or more, 4.5 ng / mL or more, 5.0 ng / mL or more, 5.5 ng / mL or more, 6.0 ng / mL or more, 6.5 ng / mL or more, 6.6 ng / mL or more, 6.7 ng / mL or more, 6.8 ng / mL or more, 6.9 ng / mL or more, 7.0 ng / mL or more, 7.5 ng / mL, 8.0 ng / mL or more, 8.5 ng / mL or more, 9.0 ng / mL or more, 9.5 ng / mL or more, 10.0 ng / mL or more, 10.5 ng / mL or more, 11.0 ng / mL or more, 11.5 ng / mL or more, 12.0 ng / mL or more, 12.5 ng / mL or more, 13.0 ng / mL or more, 13.5 ng / mL or more, 14.0 ng / mL or more, 14.5 ng / mL or more, 15.0 ng / mL or more, 15.5 ng / mL or more, 16.0 ng / mL or more, 16.5 ng / mL or more, 17.0 ng / mL or more, 17.5 ng / mL or more, 18.0 ng / mL or more, 18.5 ng / mL or more, 19.0 ng / mL or more, 19.5 ng / mL or more, or 20.0 ng / mL or more, and more preferably administered so that it is 6.5 ng / mL or more, 6.6 ng / mL or more, 6.7 ng / mL or more, 6.8 ng / mL or more, 6,9 ng / mL or more, 7.0 ng / mL or more, 7.5 ng / mL, 8.0 ng / mL or more, 8.5 ng / mL or more, 9.0 ng / mL or more, 9.5 ng / mL or more, 10.0 ng / mL or more, 10.5 ng / mL or more, 11.0 ng / mL or more more, 11.5 ng / mL or more, 12.0 ng / mL or more, 12.5 ng / mL or more, 13.0 ng / mL or more, 13.5 ng / mL or more, 14.0 ng / mL or more, 14.5 ng / mL or more, 15.0 ng / mL or more, 15.5 ng / mL or more more, 16.0 ng / mL or more, 16.5 ng / mL or more, 17.0 ng / mL or more, 17.5 ng / mL or more, 18.0 ng / mL or more, 18.5 ng / mL or more, 19.0 ng / mL or more, 19.5 ng / mL or more, or 20.0 ng / mL or more.

[0063] For example, the pharmaceutical composition of the present disclosure is preferably administered in such a way that the minimum value of Compound (2) is 1.0 ng / mL or more, 1.5 ng / mL or more, 1.9 ng / mL or more, 2.0 ng / mL or more, 2.5 ng / mL or more, 3.0 ng / mL or more, 3.5 ng / mL or more, 4.0 ng / mL or more, 4.5 ng / mL or more, 5.0 ng / mL or more, 5.5 ng / mL or more, 6.0 ng / mL or more, 6.5 ng / mL or more, 6.6 ng / mL or more, 6.7 ng / mL or more, 6.8 ng / mL or more, 6.9 ng / mL or more, or 7.0 ng / mL or more. and more preferably administered so that it is 6.5 ng / mL or Petition 870250090468, dated 03 / 10 / 2025, page 25 / 52 / 27 more, 6.6 ng / mL or more, 6.7 ng / mL or more, 6.8 ng / mL or more, 6.9 ng / mL or more, or 7.0 ng / mL or more.

[0064] The minimum value refers to the plasma concentration of Compound (2) immediately before the next administration after administration of Compound (I) or a pharmaceutically acceptable salt thereof in multiple doses. Normally, the minimum value refers to the minimum plasma concentration at steady state, but for convenience, it is also referred to as the minimum value in this specification even when steady state has not been reached. For example, when Compound (I) or a pharmaceutically acceptable salt thereof is administered repeatedly once daily for 2 days or more, the minimum value refers to the plasma concentration 24 hours after the last administration in repeated administration, and this may be referred to as the 24-hour post-dose minimum value.Furthermore, when Compound (I) or a pharmaceutically acceptable salt thereof is administered twice daily for 1 day or 2 days or more, the minimum value refers to the plasma concentration 12 hours after the last administration, and this may be called the 12-hour post-dose minimum. When Compound (I) or a pharmaceutically acceptable salt thereof is administered three times daily for 1 day or 2 days or more, the minimum value refers to the plasma concentration 8 hours after the last administration, and this may be called the 8-hour post-dose minimum. When Compound (I) or a pharmaceutically acceptable salt thereof is administered four times daily for 1 day or 2 days or more, the minimum value refers to the plasma concentration 6 hours after the last administration, and this may be called the 6-hour post-dose minimum.

[0065] In addition, the pharmaceutical composition of this disclosure may have its dosage increased or decreased based on measured values ​​of the minimum plasma concentration, and it is preferable that the Petition 870250090468, dated 03 / 10 / 2025, page 26 / 52 / 27 minimum value of the pharmaceutical composition in humans should be adjusted to 1.9 ng / mL or more, and more preferably to 6.9 ng / mL or more. The pharmaceutical composition of this disclosure is equipped with such a configuration, so that it is possible to treat this disease safely and effectively, even when systemic clearance varies greatly.

[0066] In another aspect, this disclosure provides that the pharmacokinetic characteristics of the concentration-time curve, such as the time to reach Cmax (Tmax) and the area under the plasma concentration-time curve (AUC), after single or multiple doses in humans, are examined by well-established statistical methods in the field of pharmacokinetics. The average value of pharmacokinetic parameters, such as Cmax and AUC, can be calculated by any of the geometric mean, arithmetic mean, or median methods. In this descriptive report, unless otherwise specified, the average Cmax, average AUC, and average minimum value are shown as arithmetic mean values.Even if the target average value is calculated by a method different from that in this specification, if the average value calculated according to the method of this specification for the target is within the numerical range described in the claims, the target average value is intended to belong to the numerical range described in the claims relating to this disclosure. <Agente Concomitante>

[0067] The pharmaceutical composition of this disclosure may also be used in combination with other medications that have a therapeutic and / or preventive effect on inflammatory bowel disease.

[0068] Examples of other medications with therapeutic and / or preventive effects in inflammatory bowel disease include elemental diets (e.g., Elental (trademark) (Ajinomoto Co., Inc.)), 5ASA preparations (e.g., mesalazine, salazosulfapyridine (sulfasalazine)), corticosteroids (e.g., prednisolone, betamethasone, budesonide) and Petition 870250090468, dated 03 / 10 / 2025, page 27 / 52 / 27 antibacterial agents (e.g., metronidazole).

[0069] Immunosuppressants (e.g., azathioprine, 6-mercaptopurine, cyclosporine, tacrolimus) may also be mentioned as medications to be used in combination.

[0070] Examples of anti-cytokine drugs include anti-TNFα antibodies (e.g., infliximab, adalimumab, certolizumab pegol, golimumab), anti-IL-6 receptor antibodies (e.g., tocilizumab), anti-IL-12 / 23 antibodies (e.g., ustekinumab, briakinumab), anti-IL-17 receptor antibodies (e.g., AMG 827, AIN457), anti-α4e7 antibodies (vedolizumab), and low molecular weight drugs such as IL-12 / 23 production inhibitors (e.g., STA5326), PDE-4 inhibitors (e.g., apremilast), chemokine inhibitors (e.g., vercirnon, CCX507), Janus kinase inhibitors (e.g., tofacitinib, GLPG0634), S1P agonists (e.g., KRP-203, RPC1063), and α4 integrin inhibitors (e.g., carotegrast methyl).

[0071] In addition, it can also be used in combination with other treatment methods that have a therapeutic and / or preventive effect on the above diseases, not limited to medications. For example, leukocytapheresis (e.g., GCAP, LCAP) can be mentioned.

[0072] Therefore, the pharmaceutical composition of this disclosure can be used in combination with other medications that have a therapeutic and / or preventive effect on the above diseases. Furthermore, the pharmaceutical composition of this disclosure can be used in combination with other treatment methods for the above diseases.

[0073] When used in combination with other medications, the pharmaceutical composition of this disclosure and the other medications may be administered simultaneously, consecutively, or separately with a time interval. Petition 870250090468, dated 03 / 10 / 2025, page 28 / 52 / 27

[0074] The dosage form of the medication to be used in combination is not particularly limited, such as oral agents, injections, enema preparations and suppositories, but it is preferable to use enema preparations and suppositories in combination for patients with lesions near the anus. Examples

[0075] The present disclosure will now be described specifically with reference to the Examples. However, the present disclosure is not limited to those descriptions. <Ensaio Clínico de Fase 1>

[0076] A phase 1 clinical trial was conducted to evaluate the safety, tolerability and pharmacokinetics of Compound (1) when administered orally to healthy adult men. [Clinical Trial Design]

[0077] This clinical trial was a single-center, randomized, double-blind, placebo-controlled, single-dose and multiple-dose ascending study with the primary objective of evaluating the safety and tolerability of Compound (1) when administered orally to healthy adult men.

[0078] Screening tests were conducted 28 to 3 days prior to administration of the experimental drug to confirm the eligibility of individuals, and individuals were hospitalized 2 days prior to administration. After hospitalization, tests were conducted 2 days prior to administration until the day of administration to confirm that there were no eligibility issues, and then Compound (1) or placebo was randomly assigned. The subjects in each cohort consisted of 8 people, of whom 6 were assigned to Compound (1) and 2 were assigned to placebo, and received the drug.

[0079] In the single-dose administration study, Compound (1) or placebo was administered in the fasted state. Petition 870250090468, dated 03 / 10 / 2025, p. 29 / 52 / 27

[0080] In the repeated-dose administration study, Compound (1) or placebo was administered on day 1, and Compound (1) or placebo was administered repeatedly from day 8 to day 17. Day 8, when repeated administration was initiated, corresponds to day 1 of administration (Day 1), and day 17 corresponds to day 10 of administration (Day 10).

[0081] Hard capsules (HCPs), a liquid autoemulsifying drug delivery system (L-SEDDS), and a soft capsule autoemulsifying drug delivery system (C-SEDDS) of Compound (1) and placebo were prepared as follows, repackaged at the medical institution according to the dosage for each subject, and dispensed by the pharmacy staff. [CAP Preparation]

[0082] Compound (1) at 1 mg, 10 mg or 50 mg, or crystalline cellulose as placebo at 1 mg, 10 mg or 50 mg was placed in hard capsules. [Preparation of L-SEDDS]

[0083] Polyoxyl 35 castor oil (Kolliphor EL) and propylene glycol monocaprylate (Type II) (Capryol 90) were mixed in a mass ratio of about 7:1, this mixture was mixed with about 2% ethanol by mass, compound (1) was added to the resulting mixture so as to be about 10% by mass, and the mixture was sonicated at 40°C to produce a liquid self-emulsifying drug delivery system. [Production of C-SEDDS]

[0084] Polyoxyl 35 castor oil (Kolliphor EL) and propylene glycol monocaprylate (Type II) (Capryol 90) were mixed in a mass ratio of about 7:1, this mixture was mixed with about 2% ethanol by mass, compound (1) was added to the resulting mixture so as to be about 10% by mass, and the liquid Petition 870250090468, dated 03 / 10 / 2025, page 30 / 52 / 27 self-emulsifying agent obtained by agitation at 40°C was encapsulated in soft gelatin capsules in a quantity of 1000 mg. [Measurement of Concentration (FC) of Compound (2)]

[0085] The plasma concentration of Compound (2) was measured using a validated measurement method. Specifically, plasma was separated from collected and processed blood, and then the plasma concentration was measured by an LC / MS / MS instrument. [Rate of inhibition of MAdCAM-1 (PD) binding to plasma lymphocytes and IC90, IC50]

[0086] The binding rate of MAdCAM-1 to plasma lymphocytes was measured using a validated measurement method using the obtained blood samples, and the inhibition rate of MAdCAM-1 binding to plasma lymphocytes was calculated using Excel. Specifically, 5 μL of an 80 mM MnCl2 solution was added to 90 pL of heparinized blood and incubated at room temperature for 10 minutes. A volume of 5 pL of 200 pg / mL recombinant human MAdCAM-1 / Fc (R&D Systems) was added to make a total volume of 100 pL, and the mixture was incubated at room temperature for 30 minutes. Subsequently, 1900 pL of BD Phosflow Lyse / Fix Buffer 5X (BD Biosciences) was added, and hemolysis and fixation were performed at 37°C for 10 minutes. After centrifugation for 5 minutes, the supernatant was removed and 2000 µL of RPMI-1640 medium supplemented with 10% inactivated fetal bovine serum (hereinafter referred to as the medium) was added.After centrifugation for 5 minutes, the supernatant was removed and washed. After another wash with the medium, 50 pL of Brilliant Stain Buffer (BD Biosciences), 1.25 pL of MAdCAM-1 FITC (Hycult Biotech), 5 pL of CD4 PE (BD Biosciences), 2.5 pL of CD45RO APC (UCHL1) (BioLegend), 5 pL of CD3 BV421 (SK7) (BioLegend), and 2.5 pL of CD45 BV510 (HI30) (BioLegend) were added, and the mixture was incubated for 30 minutes. After washing with buffer... Petition 870250090468, dated 03 / 10 / 2025, page 31 / 52 / 27 staining (BSA) (BD Biosciences), the percentage of MAdCAM-1 positive cells among CD3 positive and CD4 positive cells was measured using flow cytometry.

[0087] The percentage of MAdCAM-1 positive cells among CD4-positive CD3 cells was calculated by subtracting each measured value from the value measured when MAdCAM-1 / Fc was not added as a control. The percentage of MAdCAM-1 positive cells among CD4-positive CD3 cells before administration of Compound (1) or placebo was defined as 0% inhibition, and the MAdCAM-1 binding inhibition rate at each blood sampling point was obtained. In addition, the IC50 concentration that causes 50% binding inhibition and the IC90 concentration that causes 90% binding inhibition were calculated. IC90=6.9 ng / mL IC50=1.9 ng / mL [Single Dose Administration Study]

[0088] Compound (1) was administered orally once per dose and dosage form to 6, 20, 100, 200, and 400 mg hard capsules (HCP), liquid self-emulsifying drug delivery system (L-SEDDS), or soft capsule self-emulsifying drug delivery system (C-SEDDS). After administration, blood was collected and Compound (2) was quantified. Mean plasma concentrations of Compound (2) are shown in Table 1, and plasma concentration profiles are shown in Figures 1A and 1B. Table 1: Mean plasma concentrations (ng / mL) of compound (2) after single dose administration. Table 1-1 Time (h) Dosage (mg) / Dosage Form 6 / CAP 20 / CAP 100 / CAP 200 / L-SEDDS 400 / L-SEDDS 0.5 4.28 8.84 1 0.121 0.211 0.556 11.5 36.7 1.5 0.350 0.585 1.274 14.2 45.6 Petition 870250090468, dated 03 / 10 / 2025, page 32 / 52 / 27 Time (h) Dosage (mg) / Dosage Form 6 / CAP 20 / CAP 100 / CAP 200 / L-SEDDS 400 / L-SEDDS 2 0.448 0.768 1.864 13.5 45.0 2.5 0.536 1.023 2.343 13.0 40.1 3 0.554 0.926 2.246 10.9 31.8 4 0.590 0.817 2.465 9.50 22.6 5 0.424 0.702 2.331 6.46 14.3 6 0.313 0.567 1.906 3.97 8.41 7 0.209 0.533 1.498 2.89 6.54 8 0.127 0.507 1.357 2.54 4.76 12 0.075 0.351 1.276 2.07 4.34 15 0.338 1.135 2.00 3.90 21 0.339 1.046 2.11 3.98 24 0.245 1.030 2.25 3.79 Table 1-2 Time (h) Dosage (mg) / Dosage Form 200 / C-SEDDS 0.5 Below the limit of quantification 1 Below the limit of quantification 1.5 2.14 2 6.68 2.5 10.5 3 13.4 4 14.2 5 10.4 6 5.91 7 3.46 8 3.33 12 2.48 15 2.14 21 1.85 24 1.69 [Repeated Administration Study 1]

[0089] Compound (1) was repeatedly administered to 6 healthy adult men at a dose of 400 mg once daily for 10 days as LSEDDS, and blood was collected 24 hours later to quantify compound (2).

[0090] The mean plasma concentrations of Compound (2) are shown in Table 2, and the plasma concentration profile is shown in Fig. 2A. Petition 870250090468, dated 03 / 10 / 2025, page 33 / 52 / 27 Table 2: Minimum 24-hour post-dose values ​​(ng / mL) of compound (2) after repeated administration_______________________________ Day 400 / L-SEDDS Initial Value 0.000 1 5.092 2 10.90 3 10.60 4 14.21 5 19.56 6 17.27 7 19.85 8 22.03 9 22.80 10 13.04 [Repeated Administration Study 2]

[0091] Compound (1) was repeatedly administered to 6 healthy adult men at a dose of 200 mg twice daily (every 12 hours) for 10 days as C-SEDDS, and blood was collected 12 hours later to quantify compound (2).

[0092] The mean plasma concentrations of Compound (2) are shown in Table 3, and the plasma concentration profile is shown in Fig. 2B. Table 3: Minimum 12-hour post-dose values ​​(ng / mL) of compound (2) after repeated administration Day 400 (200*2) / C-SEDDS Initial Value 0.000 0.5 2.025 1 3.653 1.5 4.250 2 6.021 2.5 7.700 3 7.026 3.5 7.381 4 9.303 4.5 9.167 5 9.985 5.5 12.59 6 11.20 6.5 10.81 7 11.82 7.5 10.83 8 14.16 8.5 12.12 9 15.06 9.5 12.20 10 13.69 Petition 870250090468, dated 03 / 10 / 2025, page 34 / 52 / 27

[0093] As shown in Table 2 and Fig. 2A, with once-daily administration of L-SEDDS, the concentration was maintained above the 90% IC (6.9 mg / mL) from the second day of administration. As shown in Table 3 and Fig. 2B, with twice-daily administration of CSEDDS, the concentration was maintained above the 90% IC (6.9 mg / mL) from the third day of administration.

[0094] In addition, for once-daily administration of L-SEDDS and twice-daily administration of C-SEDDS, respectively, on day 10 (Day 10) from the start of repeated administration, blood was collected 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 12, 15, 21, and 24 hours later to quantify Compound (2). For twice-daily administration of C-SEDDS, blood was collected again 13, 14, 14.5, and 16 hours later to quantify Compound (2). The mean plasma concentration profile of Compound (2) on day 10 from the start of repeated administration is shown in Table 4, and the plasma concentration profiles are shown in Figs. 3A and 3B. Table 4: Mean plasma concentrations (ng / mL) of compound (2) on day 10 of repeated administration and after single dose administration. Table 4-1 Time (h) Single dose administration Day 10 of repeated administration 0.5 8.84 23.82 1 36.7 43.52 1.5 45.6 44.71 2 45.0 40.35 2.5 40.1 34.19 3 31.8 32.09 4 22.6 28.31 5 14.3 25.14 6 8.41 17.77 7 6.54 14.77 8 4.76 13.57 12 4.34 16.86 15 3.90 11.33 21 3.98 15.69 24 3.79 13.04 Table 4-2 Time (h) Single dose administration Day 10 of repeated administration 0.5 Below the limit of quantification 11.82 1 Below the limit of quantification 10.63 1.5 2.14 10.52 Petition 870250090468, dated 03 / 10 / 2025, page 35 / 52 / 27 Time (h) Single dose administration Day 10 of repeated administration 2 6.68 14.42 2.5 10.5 17.31 3 13.4 18.02 4 14.2 20.07 5 10.4 20.59 6 5.91 14.19 7 3.46 12.13 8 3.33 10.93 12 2.48 12.20 13 15.64 14 25.37 14.5 25.16 15 2.14 22.99 16 20.48 21 1.85 13.24 24 1.69 13.69

[0095] Table 4 (Table 4-1) and Fig. 3A show that the plasma concentration (minimum value) of Compound (2) after 24 hours on the 10th day of repeated administration increased more than threefold. This suggests that repeated administration can maintain a high plasma concentration of Compound (2).

[0096] Furthermore, Table 4 (Table 4-2) and Fig. 3B show that the plasma concentration (minimum value) of Compound (2) 12 hours after the second dose on the 10th day of repeated administration increased approximately eightfold. This suggests that dose increase and repeated administration are useful for achieving a higher plasma concentration of Compound (2).

[0097] Furthermore, regarding the minimum value of Compound (2), it was 2.25 ng / mL for a single dose of 200 mg once daily of L-SEDDS and 1.69 ng / mL for a single dose of 200 mg once daily of C-SEDDS. In single-dose administration, the resulting minimum value of C-SEDDS was approximately 75% of the resulting minimum value of L-SEDDS (Table 1), while the minimum value on day 10 resulting from repeated administration of 200 mg twice daily of C-SEDDS (13.69 ng / mL) was equal to or greater than the minimum value resulting from repeated administration of 400 mg once daily of LSEDDS (13.04 ng / mL) (Tables 2-4). This suggests that, even with the same daily dose, splitting the dose into two daily doses maintains a concentration Petition 870250090468, dated 03 / 10 / 2025, p. 36 / 52 / 27 highest plasma concentration. [PK 1 Simulation Analysis using the Superposition Method]

[0098] The plasma concentration profile of Compound (2) on day 10 of repeated administration was predicted using the superposition method implemented in the Non-Parametric Superposition (NPS) tool of the Phoenix WinNonlin analysis software, applying the single dose results (Certara LP) (Fig. 4). The average plasma concentration profile at the following time points obtained from the simulation results is shown in Table 5. Table 5: Predicted plasma concentration (ng / mL) of compound (2) on Day 10 of repeated administration__________________________________________ Time (h) 20 / CAP 100 / CAP 200 / L-SEDDS 400 / L-SEDDS 0 0.50 3.84 6.29 15.05 0.6 0.54 3.94 8.37 19.48 1.2 0.59 4.07 10.42 23.73 1.8 0.64 4.19 13.78 36.61 2.4 0.69 4.32 17.24 50.08 3 0.85 4.63 18.79 55.50 3.6 1.03 4.96 20.07 59.76 4.8 1.22 5.53 19.70 59.99 6.1 1.45 5.98 19.16 55.63 7.9 1.36 5.96 16.60 44.88 12.1 1.15 5.96 12.63 29.67 13.9 1.04 5.66 10.59 24.78 17 0.95 5.11 8.67 20.95 20 0.90 4.84 7.99 18.62 23 0.84 4.76 7.72 18.29 24 0.81 4.74 7.61 18.16 [Inhibitory Activity of EX vivo Integrin]

[0099] The inhibition rate of MAdCAM-1 (PD) lymphocyte binding in plasma was assessed using collected blood, and the correlation with the plasma concentration (PK) of Compound (2) was plotted (Fig. 5). Fig. 5 suggests that plasma concentration and inhibitory activity of the ligand are correlated. [PK 2 Simulation Analysis using the Superposition Method]

[00100] The plasma concentration of Compound (2) on day 10 of repeated administration of 200 mg twice daily (every 12 hours) was Petition 870250090468, dated 03 / 10 / 2025, page 37 / 52 / 27 predicted using the superposition method implemented in the Non-Parametric Superposition (NPS) tool of the Phoenix WinNonlin analysis software, applying the results of once-daily administration of 200 mg (Certara LP) (Fig. 6). The average plasma concentration profile at the following time points obtained from the simulation results is shown in Table 6. Table 6: Predicted plasma concentration (ng / mL) of compound (2) on day 10 of twice-daily repeated administration___________ Time (h) 200 mg* 2 times / day 0 28.3 0.5 36.5 1 50.0 1.5 55.5 1.9 54.6 2.4 53.4 2.9 49.5 4.1 44.7 5.1 38.6 6.1 33.7 7 31.4 8 30.4 12 30.6 13.6 55.9 15 48.8 21.1 30.0 24 28.8

[00101] Compared to the measured minimum value (13.04 ng / mL) after repeated administration of 400 mg once daily, the predicted minimum value (28.8 ng / mL) for repeated administration of 200 mg twice daily (minimum value 12 hours after the second dose on the 10th day of administration) maintained approximately twice the plasma concentration. This suggests that, even with the same daily dose, dividing the dose into two daily doses maintains a higher plasma concentration.

[00102] Measured and predicted Cmax and trough values ​​are shown in Table 7. Because the drug effect depends on plasma concentration, for each Cmax and trough value, IC90 (6.9 ng / mL) or higher was judged as A, IC50 (1.9 ng / mL) or higher and less than IC90 (6.9 ng / mL) as B, and less than IC50 (1.9 ng / mL) as C. Petition 870250090468, dated 03 / 10 / 2025, page 38 / 52 / 27 Table 7 Administration Period Frequency of Administration Dosage (mg) / Dosage Form Plasma Concentration (ng / mL) Judgment Cmax Minimum Value Cmax Minimum Value Measured Value Single Once daily 6 / CAP 0.59 - CC Single Once daily 20 / CAP 1.02 0.25 CC Single Once daily 100 / CAP 2.47 1.03 BC Single Once daily 200 / L-SEDDS 14.2 2.25 AB Single Once daily 200 / C-SEDDS 14.2 1.69 AC Single Once daily 400 / L-SEDDS 45.6 3.79 AB Repeated Once daily 400 / L-SEDDS 44.7 13.0 AA Repeated Twice daily 400(200*2) / C-SEDDS 25.4 13.7 AA Expected Value Repeated Once a day 20 / CAP 1.45 0.81 CC Repeated Once a day 100 / CAP 6.09 4.74 BB Repeated Once a day 200 / L-SEDDS 20.1 7.61 AA Repeated Once a day 400 / L-SEDDS 60.3 18.2 AA Repeated Twice a day 400(200*2) / L-SEDDS 55.9 28.8 AA

[00103] Furthermore, since the predicted Cmax on day 10 of repeated administration of 20 mg was 1.45 ng / mL and the predicted minimum value 24 hours after the dose was 0.81 ng / mL, it was estimated that the Cmax on day 10 of repeated administration of 50 mg, which is 2.5 times the amount, would be 3.63 ng / mL and the minimum value would be 2.03 ng / mL. These values ​​were above the IC50 (1.9 ng / mL) and can be judged as B. Petition 870250090468, dated 03 / 10 / 2025, pp. 39 / 52

Claims

1 / 3 CLAIMS 1. Pharmaceutical composition for the treatment of inflammatory bowel disease, characterized in that it comprises a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 50 mg or more per day as an active ingredient, (I) where R represents a hydroxyl group or an isobutyloxy group.

2. Pharmaceutical composition according to claim 1, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 100 mg or more per day as the active ingredient.

3. Pharmaceutical composition according to claim 1, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 200 mg or more per day as the active ingredient.

4. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that it is an oral dosage form.

5. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more.

6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered 1 to 5 times daily.

7. Pharmaceutical composition according to any one of claims 1 to 6, characterized in that it is in the form of a self-emulsifying preparation.

8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more, such that a plasma concentration as a minimum value of the compound represented by the following formula (2) is 1.9 ng / mL or more.

9. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered repeatedly for 2 days or more, such that a plasma concentration as a minimum value of the compound represented by formula (2) above is 6.9 ng / mL or more.

10. Pharmaceutical composition according to any one of claims 1 to 9, characterized by the fact that the inflammatory bowel disease Petition 870250090468, dated 03 / 10 / 2025, page 41 / 52 3 / 3 is ulcerative colitis.

11. Pharmaceutical composition according to any one of claims 1 to 10, characterized in that the compound or a pharmaceutically acceptable salt thereof is administered to a human being at a dose of 800 mg or less per day as the active ingredient. Petition 870250090468, dated 03 / 10 / 2025, pp. 42 / 52

Images