Self-emulsifying composition and self-emulsifying preparation containing sulfonamide derivative

Abstract

Provided is a pharmaceutical composition containing a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and having improved absorption during oral administration. Disclosed is a self-emulsifying composition comprising a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two solubilizing agents.

Description

Self-emulsifying composition and self-emulsifying preparation containing sulfonamide derivative

[0001] The present disclosure relates to self-emulsifying compositions and formulations containing sulfonamide derivatives.

[0002] In general, compounds with a molecular weight of 500 or greater are known to have low water solubility and low membrane permeability upon oral administration (Donovan, MD et al. (1990) Absorption of polyethylene glycols 600 through 2000: The molecular weight dependence of gastrointestinal and nasal absorption. Pharm. Res. 7, 863-868). When preparing pharmaceuticals containing such compounds, their low solubility and membrane permeability in the gastrointestinal tract after oral administration can lead to poor absorption. Therefore, various pharmaceutical innovations have been developed to improve compound absorption. One such innovation is the self-emulsifying drug delivery system (SEDDS), which is composed of oils and surfactants. SEDDS is a formulation prepared by uniformly mixing, dissolving, or dispersing active ingredients in the absence of water. When SEDDS is orally administered, it disperses and dissolves in the water in the digestive tract to form an emulsion, which is expected to improve the solubility and membrane permeability of the compounds contained therein and thereby improve absorption.

[0003] JP 2021-169476 A discloses that the applicability of SEDDS was examined for low membrane permeability medium molecular weight compounds, JP 2022-540780 A discloses that the applicability of SEDDS was examined for tetrahydropyrazolopyrimidinone compounds, and JP 2021-107433 A discloses that the applicability of SEDDS was examined for ω3 polyunsaturated fatty acids as a means of improving membrane permeability and absorbability.

[0004] It has been reported that a sulfonamide derivative represented by the following formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof has an α4 integrin inhibitory activity and is useful as a pharmaceutical for treating or preventing inflammatory bowel disease and the like (WO 2017 / 135472). However, until now, there has been insufficient knowledge about the membrane permeability and absorbability of the compound having a molecular weight of 500 or more.

[0005] Even if the molecular weight is 500 or more, physical properties such as solubility and membrane permeability vary depending on the compound, and it is unclear whether the use of SEDDS improves the absorbability of the compound. Furthermore, it is unclear which component should be combined with the compound to prepare a SEDDS with improved solubility and membrane permeability.

[0006] The present inventors have investigated the sulfonamide derivatives represented by the above formula (1), their pharmaceutically acceptable salts, or their active metabolites, and have found that there is room for improvement in the blood exposure level when the compounds are simply orally administered in powder or suspension form. In other words, further improvement in membrane permeability and absorbability is required.

[0007] The present disclosure was discovered by the present inventors in light of the above circumstances and through extensive ingenuity, and one of the objects of the present disclosure is to provide a pharmaceutical composition containing a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and having improved absorbability when orally administered.

[0008] In order to solve the above problems, the present inventors have conducted various studies and discovered that the absorbability of the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof can be improved by preparing a self-emulsifying composition containing the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two types of solubilizers, thereby completing the invention.

[0009] Non-limiting aspects of the present disclosure provide the following technical idea: [1] A compound represented by the following formula (1): A self-emulsifying composition comprising a sulfonamide derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two solubilizing agents. [2] The self-emulsifying composition according to [1] above, wherein the at least two solubilizing agents comprise at least one surfactant and at least one co-surfactant. [3] The self-emulsifying composition according to [1] above, wherein the solubilizing agent comprises at least two agents selected from the group consisting of cyclodextrin or a derivative thereof, bile acid or a derivative thereof, a fatty alcohol, a fatty acid or a derivative thereof, and a tocol derivative. [4] The self-emulsifying composition according to [2] above, wherein the surfactant comprises at least one agent selected from the group consisting of polyglyceryl-2 dioleate, polyglyceryl-3 dioleate, polyglyceryl-10 trioleate, propylene glycol monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl dilaurate, and glyceryl monolinoleate. [5] The co-surfactant may be selected from the group consisting of polyoxyl 40 castor oil, polyoxyl 35 castor oil, 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, caprylic / capric PEG-8 glyceride, lauroyl polyoxyl-32 glyceride, linoleoyl polyoxyl-6 glyceride, oleoyl polyoxyl-6 glyceride, stearoyl polyoxyl-32 glyceride, linoleoyl polyoxyl-6 glyceride, oleoyl polyoxyl-6 glyceride, stearoyl polyoxyl-32 glyceride, oleoyl polyoxyl-6 ... The self-emulsifying composition according to [2] above, which comprises at least one selected from the group consisting of oxyl-32 glyceride, caprylic / capric acid PEG-6 glyceride, polyglyceryl-10 monooleate, polyglyceryl-10 laurate, polyglyceryl-15 hydroxystearate, α-tocopherol PEG 400 succinate, α-tocopherol PEG 1000 succinate, dl-α-tocopherol PEG 1000 succinate, and d-α-tocopherol PEG 1000 succinate.[6] The self-emulsifying composition according to any one of [2], [4], and [5], wherein the content of the surfactant is 0.1 times or more the mass % of the sulfonamide derivative represented by formula (1) or a pharmaceutically acceptable salt thereof, and the content of the co-surfactant is 10 times or less the mass % of the sulfonamide derivative represented by formula (1) or a pharmaceutically acceptable salt thereof. [7] The self-emulsifying composition according to any one of [2] and [4] to [6], wherein the ratio of the surfactant to the co-surfactant is 1:1 to 8:1. [8] The self-emulsifying composition according to any one of [2] and [4] to [7], wherein the surfactant comprises propylene glycol monocaprylate. [9] The self-emulsifying composition according to any one of [2] and [4] to [8], wherein the co-surfactant comprises polyoxyl 40 castor oil, polyoxyl 35 castor oil, or polyoxyethylene castor oil.

[10] The self-emulsifying composition according to any one of [1] to [9] above, further comprising a cosolvent.

[11] A self-emulsifying preparation in a dosage form suitable for oral administration, comprising the self-emulsifying composition according to any one of [1] to

[10] above.

[12] The self-emulsifying preparation according to

[11] above, in the dosage form of a capsule.

[0010] Furthermore, as another aspect of the present disclosure, the following technical idea is also provided. [2-1] A therapeutic or preventive agent for a disease, comprising a self-emulsifying composition containing a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two solubilizing agents. [2-2] The therapeutic or preventive agent according to [2-1] above, wherein the disease is an inflammatory disease in which an α4 integrin-dependent adhesion process is involved in the pathology. [2-3] The therapeutic or preventive agent according to [2-1] or [2-2] above, wherein the disease is rheumatoid arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular disease, arteriosclerosis, restenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection. [2-4] The therapeutic or preventive agent according to [2-3] above, wherein the disease is ulcerative colitis or Crohn's disease. [2-5] A method for treating or preventing a disease using a self-emulsifying composition comprising a compound represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two solubilizers. [2-6] The method according to [2-5] above, wherein the disease is an inflammatory disease in which an α4 integrin-dependent adhesion process is involved in the pathology. [2-7] The method according to [2-5] or [2-6] above, wherein the disease is rheumatoid arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular disease, arteriosclerosis, restenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection. [2-8] The method according to [2-7] above, wherein the disease is ulcerative colitis or Crohn's disease. [2-9] Use of the self-emulsifying composition according to any one of [1] to

[10] above for the manufacture of a therapeutic or preventive agent for an inflammatory disease in which an α4 integrin-dependent adhesion process is involved in the pathology.[2-10] The use according to [2-9] above, wherein the disease is rheumatoid arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergy, diabetes, cardiovascular disease, arteriosclerosis, restenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection. [2-11] The use according to [2-10] above, wherein the disease is ulcerative colitis or Crohn's disease. [2-12] The self-emulsifying composition according to [3] above, wherein the fatty acid or a derivative thereof is an amide ester of a fatty acid, an ester of a fatty acid and a hydroxy acid, a sugar ester or sugar ester derivative of a fatty acid, an ester of a fatty acid and a propylene glycol, an ester of a fatty acid and a glycerol, an ester of a fatty acid and a polyglycerol, an ester of a fatty acid and an ethylene glycol, an ester of a fatty acid and a polyethylene glycol, or an ester of a fatty acid and a macrogolglycerin.

[0011] Furthermore, the following technical idea is also provided as another aspect of the present disclosure. [3-1] A self-emulsifying composition comprising a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and at least two solubilizers, wherein the total content of the solubilizers is 10% by mass or more and 90% by mass or less, relative to the total mass of the self-emulsifying composition. [3-2] The self-emulsifying composition according to [3-1] above, wherein the total content of the solubilizers is 20% by mass or more and 90% by mass or less, relative to the total mass of the self-emulsifying composition. [3-3] The self-emulsifying composition according to [3-1] above, wherein the total content of the solubilizers is 30% by mass or more and 90% by mass or less, relative to the total mass of the self-emulsifying composition. [3-4] The self-emulsifying composition according to [3-1] above, wherein the total content of the solubilizers is 40% by mass or more and 90% by mass or less, relative to the total mass of the self-emulsifying composition. [3-5] The self-emulsifying composition according to any one of [3-1] to [3-4], wherein the solubilizer comprises at least one surfactant, and the content of the surfactant is 5% by mass or more and 85% by mass or less, relative to the total mass of the self-emulsifying composition. [3-6] The self-emulsifying composition according to any one of [3-1] to [3-4], wherein the solubilizer comprises at least one surfactant, and the content of the surfactant is 10% by mass or more and 80% by mass or less, relative to the total mass of the self-emulsifying composition. [3-7] The self-emulsifying composition according to any one of [3-1] to [3-5], wherein the solubilizer comprises at least one co-surfactant, and the content of the co-surfactant is 5% by mass or more and 85% by mass or less, relative to the total mass of the self-emulsifying composition. [3-8] The self-emulsifying composition according to any one of [3-1] to [3-4] and [3-6], wherein the solubilizer comprises at least one co-surfactant, and the content of the co-surfactant is 10% by mass or more and 80% by mass or less, based on the total mass of the self-emulsifying composition. [3-9] The self-emulsifying composition according to

[10] , wherein the co-solvent is one selected from the group consisting of acetic acid, sorbitol, mannitol, glycerol, triacetin, triethyl citrate, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, propylene carbonate, ethanol, and propylene glycol.[3-10] The self-emulsifying composition according to [3-9] above, wherein the co-solvent is ethanol or propylene glycol. [3-11] The self-emulsifying composition according to any one of

[10] , [3-9], and [3-10] above, wherein the co-solvent is 10% by mass or less, relative to the total mass of the self-emulsifying composition. [3-12] The self-emulsifying composition according to [3-11] above, wherein the co-solvent is 8% by mass or less, relative to the total mass of the self-emulsifying composition. [3-13] The self-emulsifying composition according to [3-12] above, wherein the co-solvent is 5% by mass or less, relative to the total mass of the self-emulsifying composition. [3-14] The self-emulsifying composition according to any one of [1] to

[10] above, further comprising an additive. [3-15] The self-emulsifying composition according to [3-14] above, wherein the additive is at least one selected from the group consisting of excipients, lubricants, binders, pH adjusters, flavoring agents, thickeners, buffers, colorants, diluents, preservatives, and sweeteners. [3-16] The self-emulsifying composition according to [2] or [4] above, wherein the mass ratio of the sulfonamide derivative represented by formula (1) or a pharmaceutically acceptable salt thereof to the surfactant is 1:1 to 1:8. [3-17] The self-emulsifying composition according to [2] or [5] above, wherein the mass ratio of the sulfonamide derivative represented by formula (1) or a pharmaceutically acceptable salt thereof to the co-surfactant is 1:1 to 1:8. [3-18] A self-emulsifying composition containing 10 to 1,000 mg of the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof.

[0012] The present disclosure provides a self-emulsifying composition containing at least two solubilizers for a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, thereby making it possible to improve the absorbability of the compound, a pharmaceutically acceptable salt thereof, or an active metabolite thereof.

[0013] Logarithm of AUC of the Tube method (Tube method Log(AUC 0-2.25 )) and the logarithm of AUC of plasma concentration (rat PO / PK Log(AUC)). 0-2.25)) and dissolution rate (%) at pH 2.4. 0-2.25 )) and dissolution rate (%) at pH 6.4.

[0014] The present disclosure will be described in detail below. Note that the following embodiment is one aspect of the present disclosure and does not limit the scope of the present disclosure.

[0015] In the present disclosure, the sulfonamide derivative represented by the following formula (1) (sometimes referred to herein as "compound (1)") has an α4 integrin inhibitory activity and is a compound also known as 2-methylpropyl(2S)-2-{2,5-difluoro-4-[4-(2,2-dimethylpropylamido)phenylsulfonamido]benzamido}-3-{2-[1,6-dimethyl-2,4-dioxo-1,4-dihydropyrimidin-3(2H)-yl]pyridin-5-yl}propanoic acid. Those skilled in the art will be able to recognize the scope of the present disclosure regardless of the nomenclature used, as long as they refer to the above compound. This compound can be obtained by known methods, and examples of synthesis methods include, but are not limited to, the methods described in WO 2017 / 135472.

[0016]

[0017] In the present disclosure, the term "pharmaceutically acceptable salt" refers to any salt that can form a salt of the sulfonamide derivative represented by formula (1) above while retaining its pharmacological activity. For example, with respect to an acidic group such as a carboxyl group in the formula, 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. With respect to a basic group in the formula, 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 with organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid. Furthermore, known methods can be used as appropriate for forming the salt. For example, the sulfonamide derivative represented by formula (1) can be mixed with a necessary acid or base in an appropriate ratio in a solvent or dispersion medium, or the salt can be converted from another salt form by a method such as ion exchange.

[0018] In the present disclosure, the term "active metabolite" refers to a group of compounds that have an α4 integrin inhibitory effect and are converted from the sulfonamide derivative represented by formula (1) by enzymes, gastrointestinal fluids, etc. under physiological conditions in vivo. Conversion reactions include oxidation, reduction, hydrolysis, etc. Non-limiting examples of active metabolites include the compound represented by formula (2) below (sometimes referred to as "compound (2)" in this specification).

[0019]

[0020] The term "self-emulsifying composition" refers to a composition that has the property of being able to form an emulsion and emulsify in an aqueous medium (self-emulsifying property), and includes self-nanoemulsifying compositions and self-microemulsifying compositions. The emulsion formed may be of any size, so self-emulsifying emulsion drug delivery systems (SEDDS), self-emulsifying microemulsion drug delivery systems (SMEDDS), and self-emulsifying nanoemulsion drug delivery systems (SNEDDS), which are generally distinguished by the diameter of the emulsion, all fall within the scope of the self-emulsifying composition of the present disclosure.

[0021] The self-emulsifying composition of the present disclosure can be prepared by a known method. The properties of the prepared self-emulsifying composition can be evaluated by a known method as appropriate. In a non-limiting aspect of evaluating the properties of a self-emulsifying composition, for example, particle size is known as an index representing the physical properties of an emulsion. A conventionally known method can be used to evaluate particle size. For example, dynamic light scattering (DLS) can be used. In addition, a method of evaluating turbidity using a turbidimeter as a parameter reflecting particle size can also be used.

[0022] In the self-emulsifying composition of the present disclosure, the content of the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite is not particularly limited, but is preferably 10 mg or more, more preferably 50 mg or more, even more preferably 100 mg or more, and also preferably 1000 mg or less, more preferably 800 mg or more, and even more preferably 400 mg or less. Furthermore, in the self-emulsifying composition of the present disclosure, the content of the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite is preferably 10 to 1000 mg, more preferably 50 to 800 mg, and even more preferably 100 to 400 mg. When the total mass of the self-emulsifying composition of the present disclosure is taken as 100%, the content of the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite is preferably 1% by mass or more, more preferably 5% by mass or more, and also preferably 50% by mass or less, more preferably 30% by mass or less.

[0023] The self-emulsifying composition of the present disclosure contains at least two solubilizing agents. The term "solubilizing agent" refers to an appropriate medium capable of increasing the solubility of a target solute. Any known solubilizing agent is not particularly limited within the scope of the present disclosure, but preferred solubilizing agents include cyclodextrins (e.g., β-cyclodextrin, γ-cyclodextrin), cyclodextrin derivatives (e.g., sulfobutyl or hydroxypropyl ether), bile acids, bile acid derivatives (e.g., cholate, ursodeoxycholate, chenodeoxycholate, taurochenodedeoxycholate, tauroursodeoxycholate, glycochenodedeoxycholate, or glycoursodeoxycholate). solubilizers belonging to any of the following groups: fatty acids (e.g., capric acid, caprylic acid, lauric acid, sarcosinic acid, palmitic acid, myristic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, ricinoleic acid, arachidonic acid, behenic acid, and their corresponding pharmaceutically acceptable salts), fatty acid derivatives, alcohols, fatty alcohols (e.g., stearyl alcohol), fatty alcohol derivatives (e.g., polyethylene glycol octadecyl ether), and tocol derivatives.Preferred fatty acid derivatives include dioctyl sodium sulfosuccinate, sodium lauryl sulfate, amide esters of fatty acids (e.g., lauric acid diethanolamide, sodium lauryl sarcosinate, lauroylcarnitine, palmitoylcarnitine, or myristoylcarnitine), esters of fatty acids or fatty alcohols with hydroxy acids (e.g., sodium stearoyl lactylate, lauryl lactate), sugar esters and sugar ester derivatives of fatty acids (e.g., glucose monocaprylate, diglucose monocaprylate, sucrose laurate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan monooleate, sorbitan monostearate, sorbitan tristearate, sucrose mirin), and the like. Examples of fatty acid esters include esters of fatty acids and propylene glycol, esters of fatty acids and glycerol, esters of fatty acids and polyglycerol, esters of fatty acids and ethylene glycol, esters of fatty acids and polyethylene glycol, esters of fatty acids and macrogolglycerin (also called polyoxyglycerin), triglycerides (e.g., corn oil, almond oil, coconut oil, castor oil, hydrogenated castor oil, hydrogenated coconut oil), mixtures of esters of fatty acids and propylene glycol and esters of fatty acids and macrogolglycerin, and polyglyceridized fatty acids.

[0024] The total content of solubilizers can be blended at any ratio as long as they form an emulsion and exhibit self-emulsification.For example, the total content of solubilizers can be 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more, when the total mass of the self-emulsifying composition is 100%.For example, the total content of solubilizers can be 90% by mass or less, when the total mass of the self-emulsifying composition is 100%.Although not limited thereto, when the total mass of the self-emulsifying composition is 100%, the total content of solubilizers can be 10% by mass or more and 90% by mass or less.Preferably, it can be 20% by mass or more and 90% by mass or less, more preferably 30% by mass or more and 90% by mass or less, even more preferably 40% by mass or more and 90% by mass or less, even more preferably 50% by mass or more and 90% by mass or less, and particularly preferably 60% by mass or more and 90% by mass or less.

[0025] Also, in one aspect of the present disclosure, the solubilizer comprises at least one surfactant and at least one co-surfactant.

[0026] The term "surfactant" refers to a group of solubilizers that exhibit lipophilicity. As an index of lipophilicity, the hydrophile-lipophile balance (HLB) can be used, although it is not limited thereto. The HLB is calculated by dividing substances that do not have hydrophilic groups into equal parts, with HLB = 0 for substances that do not have lipophilic groups and HLB = 20 for substances that do not have lipophilic groups. This can be calculated by methods known to those skilled in the art, such as the Griffin method. In the present disclosure, HLB refers to the value calculated by the Griffin method. Generally, the smaller the HLB, the higher the lipophilicity. Therefore, in the self-emulsifying composition of the present disclosure, a solubilizer with a relatively low HLB can be appropriately selected as the surfactant. For example, in the present disclosure, a "surfactant" having an HLB of 7 or less may be selected. Specifically, these surfactants include esters of fatty acids and propylene glycol, esters of fatty acids and glycerol, and esters of fatty acids and polyglycerol (HLB≦7). More specifically, these surfactants include polyglyceryl-2 dioleate, polyglyceryl-3 dioleate, polyglyceryl-10 trioleate, propylene glycol monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl dilaurate, and glyceryl monolinoleate. These surfactants may be synthesized by known methods or may be commercially available. Non-limiting examples of commercially available surfactants include those commercially available with names such as Caprol, Capryol, Capmul, Lauroglycol, and Plurol Oleique included in their product names. These surfactants may be used alone or in combination of two or more.

[0027] When the total mass of the self-emulsifying composition of the present disclosure is taken as 100%, the surfactant content is preferably 5% by mass or more, more preferably 10% by mass or more, and preferably 85% by mass or less, more preferably 80% by mass or less. Furthermore, when the content of the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite is taken as 1 in terms of the sulfonamide derivative represented by formula (1), the surfactant content is 0.1 or more, preferably 0.5 or more, more preferably 1.0 or more, and 10 or less, preferably 9.5 or less, more preferably 9 or less. Furthermore, the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite, and the surfactant can be contained in a mass ratio within the range of 1:1 to 1:10, preferably 1:1 to 1:8.

[0028] The term "co-surfactant" refers to a group of solubilizers that exhibit hydrophilicity. Generally, the higher the HLB, the higher the hydrophilicity. Therefore, in the self-emulsifying composition of the present disclosure, a solubilizer with a relatively high HLB can be appropriately selected as the co-surfactant. For example, in the present disclosure, a solubilizer with an HLB of greater than 7 can be selected as the "co-surfactant." Specifically, they are esters of fatty acids and polyglycerol (HLB>7), esters of fatty acids and ethylene glycol, esters of fatty acids and polyethylene glycol, esters of fatty acids and macrogolglycerol, fatty alcohol derivatives or tocol derivatives, and more specifically, they are polyoxyl 40 castor oil, polyoxyl 35 castor oil, PEG-25 trioleate, PEG-60 corn glyceride, PEG-60 almond oil, PEG-40 palm kernel oil, PEG-50 castor oil, PEG-50 hydrogenated castor oil, PEG-60 hydrogenated castor oil, caprylic / capric acid PEG-8 glyceride, la Examples of the co-surfactant include uroyl polyoxyl-32 glyceride, linoleoyl polyoxyl-6 glyceride, oleoyl polyoxyl-6 glyceride, stearoyl polyoxyl-32 glyceride, caprylic / capric acid PEG-6 glyceride, polyglyceryl-10 monooleate, polyglyceryl-10 laurate, polyglyceryl-15 hydroxystearate, and α-tocopherol PEG succinate (e.g., α-tocopherol PEG 400 succinate, α-tocopherol PEG 1000 succinate, dl-α-tocopherol PEG 1000 succinate, and d-α-tocopherol PEG 1000 succinate). These co-surfactants may be synthesized by known methods or may be commercially available. Non-limiting examples of commercially available products include those commercially available with names including Kolliphor, Cremophor, Labrafil, Labrasol, Gellucire, TPGS, etc. These co-surfactants may be used alone or in combination of two or more.

[0029] Among the co-surfactants exemplified above, examples of the esters of fatty acids and macrogolglycerin include polyoxyl 40 castor oil, polyoxyl 35 castor oil, PEG-25 trioleate, PEG-60 corn glyceride, PEG-60 almond oil, caprylic / capric acid PEG-8 glyceride, lauroyl polyoxyl-32 glyceride, linoleoyl polyoxyl-6 glyceride, oleoyl polyoxyl-6 glyceride, stearoyl polyoxyl-32 glyceride, and caprylic / capric acid PEG-6 glyceride; Examples of esters of acids and polyglycerols include polyglyceryl-10 monooleate, polyglyceryl-10 laurate, and polyglyceryl-15 hydroxystearate, examples of esters of fatty acids and polyethylene glycols include PEG-50 hydrogenated castor oil and PEG-60 hydrogenated castor oil, and examples of tocol derivatives include α-tocopherol PEG 400 succinate, α-tocopherol PEG 1000 succinate, dl-α-tocopherol PEG 1000 succinate, and d-α-tocopherol PEG 1000 succinate. For esters of fatty acids and macrogolglycerol, the average number of moles of polyethylene glycol added is preferably 20 or more, and more preferably 32 or more. Examples of the esters of fatty acids and macrogolglycerin having an average number of polyethylene glycol moles added of 32 or more include polyoxyl 40 castor oil, polyoxyl 35 castor oil, PEG-60 corn glyceride, PEG-60 almond oil, lauroyl polyoxyl-32 glyceride, and stearoyl polyoxyl-32 glyceride.

[0030] When the total mass of the self-emulsifying composition of the present disclosure is taken as 100%, the content of the co-surfactant is preferably 5% by mass or more, more preferably 10% by mass or more, and preferably 85% by mass or less, more preferably 80% by mass or less. Furthermore, when the content of the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite is taken as 1 in terms of the sulfonamide derivative represented by formula (1), the content of the co-surfactant is 0.1 or more, preferably 0.5 or more, more preferably 1.0 or more, and 10 or less, preferably 9.5 or less, more preferably 9 or less. Furthermore, the sulfonamide derivative represented by formula (1), its pharmaceutically acceptable salt, or its active metabolite, and the co-surfactant can be contained in a mass ratio within the range of 1:1 to 1:10, preferably 1:1 to 1:8.

[0031] The surfactant and co-surfactant can be blended in any ratio as long as they form an emulsion and exhibit self-emulsifying properties. For example, the ratio of surfactant to co-surfactant can be 1:1 or more, 1:2 or more, or 1:3 or more. For example, the ratio of surfactant to co-surfactant can be 1:10 or less, 1:9 or less, or 1:8 or less. Although not limited thereto, the ratio of surfactant to co-surfactant is, for example, 1:1 or more and 1:10 or less, preferably 1:2 or more and 1:9 or less, and more preferably 1:3 or more and 1:8 or less.

[0032] In addition, the total content of the surfactant and the co-surfactant can be blended in any ratio as long as it forms an emulsion and exhibits self-emulsification.For example, the total content of the surfactant and the co-surfactant can be 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, or 50% by mass or more, when the total mass of the self-emulsifying composition is 100%.For example, the total content of the surfactant and the co-surfactant can be 90% by mass or less, when the total mass of the self-emulsifying composition is 100%.Although not limited thereto, when the total mass of the self-emulsifying composition is 100%, the total content of the surfactant and the co-surfactant can be 10% by mass or more and 90% by mass or less.Preferably, it can be 20% by mass or more and 90% by mass or less, more preferably 30% by mass or more and 90% by mass or less, even more preferably 40% by mass or more and 90% by mass or less, even more preferably 50% by mass or more and 90% by mass or less, and particularly preferably 60% by mass or more and 90% by mass or less.

[0033] The self-emulsifying composition of the present disclosure may further contain a cosolvent. Examples of cosolvents include acetic acid, sorbitol, mannitol, glycerol, triacetin, triethyl citrate, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, propylene carbonate, ethanol, and propylene glycol. These cosolvents may be synthesized by known methods or may be commercially available. Furthermore, only one type of cosolvent may be used, or two or more types may be combined.

[0034] In the self-emulsifying composition of the present disclosure, co-solvent can be blended in any proportion, as long as the self-emulsifying composition forms an emulsion and exhibits self-emulsification.In addition, from the viewpoint of commercial production and clinical use of the self-emulsifying preparation comprising the self-emulsifying composition of the present disclosure, it is desirable that the proportion be as small as possible.For example, but not limited to, when the total mass of the self-emulsifying composition is taken as 100%, the co-solvent can be 1% by mass or more and 15% by mass or less.Preferably, it can be 1% by mass or more and 10% by mass or less, more preferably 1% by mass or more and 8% by mass or less, even more preferably 1% by mass or more and 5% by mass or less, and particularly preferably 2% by mass.

[0035] In the self-emulsifying composition of the present disclosure, the preferred combination of surfactant, co-surfactant, and co-solvent is not particularly limited as long as it dissolves the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and exhibits self-emulsifying properties. For example, a combination of an ester of a fatty acid and propylene glycol as the surfactant, an ester of a fatty acid and macrogolglycerin or a tocol derivative as the co-surfactant, and ethanol as the co-solvent is preferred, a combination of propylene glycol monolaurate or propylene glycol monocaprylate as the surfactant, polyoxyl 40 castor oil, polyoxyl 35 castor oil, or α-tocopherol PEG 1000 succinate as the co-surfactant, and ethanol as the co-solvent is more preferred, and a combination of propylene glycol monocaprylate as the surfactant, polyoxyl 35 castor oil as the co-surfactant, and ethanol as the co-solvent is particularly preferred.

[0036] In the self-emulsifying composition of the present disclosure, the preferred blending ratio of surfactant, co-surfactant, and co-solvent is not particularly limited as long as it dissolves the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof, and exhibits self-emulsifying properties. For example, the surfactant:co-surfactant:co-solvent ratio is preferably any of 45:45:10, 40:50:10, 30:60:10, 22.5:67.5:10, 10:80:10, 11:84:5, or 11:87:2, more preferably 10:80:10, 11:84:5, or 11:87:2, with 11:87:2 being particularly preferred.

[0037] The self-emulsifying composition of the present disclosure can further contain additives. The additives are pharmaceutically acceptable and are not particularly limited as long as the self-emulsifying composition exhibits self-emulsifying properties. Examples include excipients, lubricants, binders, pH adjusters, flavoring agents, thickeners, buffers, colorants, diluents, preservatives, and / or sweeteners. These additives can be used alone or in combination of two or more known additives as appropriate. The amount of these additives can be appropriately blended in any ratio as long as the self-emulsifying composition exhibits self-emulsifying properties.

[0038] The self-emulsifying composition of the present disclosure can be formulated by known methods as appropriate and used as a self-emulsifying formulation for the treatment or prevention of the diseases described below. Preferably, various formulation techniques can be used in the formulation process as long as the composition can be used as an SEDDS, SMEDDS, and / or SNEDDS and exhibits self-emulsifying properties. More preferably, a formulation technique capable of preparing a dosage form suitable for oral administration can be selected. Here, "a dosage form suitable for oral administration" refers to any of the following forms: a solution, an aqueous or oily suspension, a syrup, an elixir, an emulsion, a tablet, a pill, a pellet, a granule, a fine granule, a powder, a capsule containing granules, fine granules, or powder, a capsule containing a solution or suspension, a sustained-release formulation, and the like. More preferably, the dosage form suitable for oral administration is a capsule, which may be either a capsule containing fine granules or powder, or a capsule containing a solution or suspension.

[0039] The capsule may be either a hard capsule or a soft capsule, but is preferably a soft capsule. The composition of the capsule shell of the soft capsule is not necessarily limited, and examples of the main components include gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropyl cellulose, etc., as well as various known components, but gelatin is preferred. There is no particular limitation on the gelatin as long as it is commercially available.

[0040] The self-emulsifying composition of the present disclosure can be used as a therapeutic or preventive agent having α4 integrin inhibitory activity by containing the sulfonamide derivative represented by the above formula (1), its pharmaceutically acceptable salt, or its active metabolite. Here, "treatment" refers to improving the clinical symptoms of a disease or disorder, i.e., curing the disease or disorder, reducing the severity or frequency of the clinical symptoms, or inducing or maintaining a state of remission, and includes actions taken on the treated organism to achieve these states. "Prevention" refers to reducing the risk of contracting a disease or disorder, and includes actions taken to prevent the disease from occurring in an organism that has not yet developed the disease or does not show clinical symptoms.

[0041] Diseases useful for treatment or prevention using the self-emulsifying composition of the present disclosure or a therapeutic or preventive agent containing the self-emulsifying composition include inflammatory diseases in which α4 integrin-dependent adhesion processes are involved in the pathology. Specifically, these are inflammatory diseases in which α4 integrin is involved in the adhesion process between vascular epithelial cells and inflammation-related cells. More specifically, these diseases are useful for treatment or prevention by using a sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof to inhibit α4 integrin and thereby prevent inflammation-related cells from infiltrating from vascular epithelium into tissues. Examples of such diseases include, but are not limited to, rheumatoid arthritis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, asthma, psoriasis, allergies, diabetes, cardiovascular disease, arteriosclerosis, restenosis, tumor growth, tumor metastasis, transplant rejection, and / or human immunodeficiency virus infection.

[0042] The self-emulsifying formulation or therapeutic agent of the present disclosure exhibits a useful therapeutic effect against the above-mentioned diseases when orally administered in a therapeutically effective amount or a therapeutically sufficient amount. Here, the terms "therapeutically effective amount" and "therapeutically sufficient amount" are synonymous and refer to an amount that is effective or sufficient to exhibit pharmacological efficacy when administered to a living body to treat a disease, and can be determined in various ways depending on the sex, age, physique, type of disease, severity of disease, lifestyle, etc. of the living body.

[0043] The self-emulsifying composition, self-emulsifying preparation, therapeutic agent, and / or prophylactic agent of the present disclosure emulsify upon mixing with gastrointestinal fluid after oral administration to a living body. Furthermore, emulsification allows the sulfonamide derivative represented by formula (1) or its pharmaceutically acceptable salt to be dissolved from the emulsion formed by the self-emulsifying preparation. Here, "gastrointestinal fluid" refers to liquid components secreted by a living body in the oral cavity, esophagus, stomach, small intestine, large intestine, etc., or liquid components present in the gastrointestinal tract, specifically saliva, gastric acid, bile, pancreatic juice, intestinal fluid, etc. Since these gastrointestinal fluids have various liquid properties ranging from acidic conditions to neutral conditions, a self-emulsifying formulation preferably has the property of eluting a compound from the formed emulsion while passing through the gastrointestinal tract after oral administration, more preferably has the property of eluting a compound from the formed emulsion in any pH range from acidic conditions to neutral conditions exhibited by the gastrointestinal fluid, even more preferably has the property of eluting a compound from the formed emulsion in a wide pH range from acidic conditions to neutral conditions, and particularly preferably has the property of eluting a compound from the formed emulsion in a wide pH range from acidic conditions to neutral conditions, and eluting a larger amount of compound under acidic conditions than under neutral conditions. Here, acidic conditions typically refer to conditions in the stomach where the formulation is mixed with gastric acid, generally referring to a pH of about 2.0 to 3.0. Furthermore, neutral conditions typically refer to a state in the small intestine or large intestine where the formulation is mixed with bile, pancreatic juice, or intestinal juice, generally referring to a pH of about 6.0 to 7.5.

[0044] In one embodiment of the present disclosure, for example, the self-emulsifying formulation has the property of eluting a larger amount of the compound under acidic conditions than when the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof is dissolved in an aqueous methylcellulose solution. Also, in one embodiment of the present disclosure, for example, the self-emulsifying formulation has the property of eluting a larger amount of the compound under acidic conditions than when the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof is dissolved in a polyethylene glycol solution.

[0045] The absorbability of a self-emulsifying composition, self-emulsifying formulation, therapeutic agent, and / or prophylactic agent in the gastrointestinal tract can be determined directly or indirectly by experimental evaluation. Specifically, the self-emulsifying composition can be evaluated by exposing it to the above-mentioned acidic to neutral conditions, and can be evaluated by either in vitro or in vivo experiments. Examples of in vitro experiments include, but are not limited to, the Tube method described below. Examples of in vivo experiments include, but are not limited to, a PO / PK test in which a self-emulsifying composition is orally administered to a rodent or non-rodent, followed by blood sampling over time to analyze the blood concentrations of the active pharmaceutical ingredient and / or its active metabolites. Non-rodents typically include dogs, monkeys, or humans. By plotting the obtained blood concentration on the vertical axis and the elapsed time on the horizontal axis, a curve showing the change in blood concentration over time can be illustrated, and the area under the curve (AUC) of this curve can also be used to evaluate absorbability.

[0046] In one embodiment of the present disclosure, for example, the self-emulsifying formulation exhibits a higher AUC than when the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof is dissolved in an aqueous methylcellulose solution. Also, in one embodiment of the present disclosure, the self-emulsifying formulation preferably exhibits a higher AUC than when the sulfonamide derivative represented by formula (1), a pharmaceutically acceptable salt thereof, or an active metabolite thereof is dissolved in a polyethylene glycol solution.

[0047] From the viewpoint of simple evaluation, for example, it is preferable to use the Tube method as an in vitro experiment. In the Tube method, a solution of a self-emulsifying composition in which a certain amount of compound is dissolved is prepared, and first added to a test solution simulating the acidic conditions in the stomach, and then a small amount of the test solution is sampled after an arbitrary time has passed. Next, a test solution simulating the neutral conditions in the small intestine is added, and the same operation is repeated. Next, a test solution simulating the neutral conditions in the large intestine is further added, and the same operation is repeated. The amount of compound in each test solution thus obtained is quantified by known analytical methods such as high performance liquid chromatography, gas chromatography, supercritical fluid chromatography, and mass spectrometry, and the absorbability can be indirectly evaluated from the dissolution rate under each condition.

[0048] Here, the "elution rate" in this specification refers to a numerical value expressed as a percentage of the amount of compound eluted into a test solution from an emulsion formed after mixing a self-emulsifying composition solution with a predetermined test solution, when the amount of compound dissolved in the solution is taken as 100%. In addition, by plotting the compound concentration in the test solution obtained under each test condition on the vertical axis and the elapsed time on the horizontal axis, a curve showing the change in compound concentration in the test solution over time can be illustrated, and the AUC of this curve can also be used to evaluate absorbability.

[0049] The present invention will be described in detail below using examples.

[0050] (Production Example 1) Preparation of Self-emulsifying Compositions 1 to 84 Each surfactant, co-surfactant, and co-solvent were weighed and mixed, and the drug substance (compound (1)) was added to the resulting mixture, followed by treatment with an ultrasonic homogenizer at 50°C to prepare Self-emulsifying Compositions 1 to 84 listed in Tables 1 to 7. The values ​​in Tables 1 to 7 represent % by mass.

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058] The surfactants listed in Tables 1 to 7 above are as follows: Capryol 90: Propylene glycol monocaprylate (Type II) Capmul MCM C8: Glyceryl monocaprylate Plurol Oleique CC497: Polyglyceryl-3-diolate Lauroglycol 90: Propylene glycol monolaurate (Type II) Lauroglycol FCC: Propylene glycol monolaurate (Type I) Capryol PGMC: Propylene glycol monocaprylate (Type I)

[0059] The co-surfactants listed in Tables 1 to 7 above are as follows:・Labrasol ALF: Caprylic / Capric PEG-8 Glyceride ・Kolliphor EL: Polyoxyl 35 Castor Oil ・Kolliphor RH40: Polyoxyl 40 Castor Oil ・Kolliphor HS15: Polyglyceryl-15 Hydroxystearate ・Gelucire 44 / 14: Lauroyl Polyoxyl-32 Glyceride ・Gelucire 48 / 16: Stearoyl Polyoxyl-32 Glyceride ・Gelucire 50 / 13: Stearoyl Polyoxyl-32 Glyceride ・TPGS: d-α-Tocopheryl PEG 1000 Succinate ・Tween 80: Polysorbate 80 ・BRIJ S10: Polyethylene Glycol Octadecyl Ether ・LABRAFIL M2125CS: Linoleoyl Polyoxyl-6 Glyceride・LABRAFIL M1944CS: Oleoyl polyoxyl-6 glyceride ・Sucrose myristate ester

[0060] Table 8 shows the correspondence between the self-emulsifying compositions in Production Example 1, which have the same component composition except for the concentration and the same ratio of components excluding the drug substance. Self-emulsifying compositions 85 to 87 were prepared according to Production Example 1. Self-emulsifying composition 85 contains 1.5% by mass of the drug substance, 44.325% by mass of Capryol 90, 44.325% by mass of Labrasol ALF, and 9.85% by mass of ethanol. Self-emulsifying composition 86 contains 1.5% by mass of the drug substance, 44.325% by mass of Capryol 90, 44.325% by mass of Kolliphor EL, and 9.85% by mass of ethanol. Self-emulsifying composition 87 contains 1.5% by mass of the drug substance, 9.85% by mass of Capryol 90, 78.8% by mass of Kolliphor EL, and 9.85% by mass of ethanol.

[0061]

[0062] (Preparation Example 2) Preparation of Comparative Compositions 1 g of polyethylene glycol 400 was weighed out, and the drug substance was added thereto to give a specified concentration. The mixture was then treated with an ultrasonic homogenizer at 50°C to prepare PEG solutions with drug substance concentrations of 15 mg / g (PEG solution 1), 50 mg / g (PEG solution 2), and 100 mg / g (PEG solution 3). 1 g of 0.5% methylcellulose aqueous solution was prepared by dissolving 125 mg of methylcellulose 400 in 25 mL of purified water, to which the drug substance was added to give a specified concentration. The mixture was then treated with an ultrasonic homogenizer at 50°C to prepare MC solutions with drug substance concentrations of 15 mg / g (MC solution 1), 50 mg / g (MC solution 2), and 100 mg / g (MC solution 3).

[0063] (Evaluation 1-1) Dissolution Test: Tube Method: 1.0 mL of 0.5% methylcellulose aqueous solution was added to 1.5 mL of HCl / saline aqueous solution adjusted to pH 2.0, and the mixture was shaken at 37°C and 90 rpm to prepare a test solution. 100 mg of the test samples (self-emulsifying compositions 1-84 prepared in Production Example 1, PEG solution 2 or 3 prepared in Production Example 2, or MC solution 2) was added to the test solution, mixed by inversion, and then shaken at 37°C and 90 rpm. 15 minutes after adding the test sample, 500 μL of the test solution was sampled, and the sampled solution was immediately filtered through a filter-integrated filtration vial (Mini-UniPrep, pore size 0.45 μm). 100 μL of the centrifuged supernatant was mixed with 100 μL of acetonitrile and 600 μL of a water / acetonitrile mixture (1:1) to prepare a gastric stage sample (pH 2.4). After sampling the gastric stage sample, 7.5 mL of FaSSIF, preheated to 37°C, was added and the mixture was shaken at 37°C and 90 rpm. 500 μL of the test solution was sampled 30 minutes, or 30, 60, 90, and 120 minutes after the addition of FaSSIF. The sampled solution was immediately filtered through a filter-integrated filtration vial (Mini-UniPrep, pore size 0.45 μm). 200 μL of the supernatant was centrifuged, and 200 μL of acetonitrile was added to obtain a small intestinal stage sample (pH 6.4). Each sample was analyzed by high-performance liquid chromatography to measure the drug dissolution rate in the gastric or small intestinal stage. The high-performance liquid chromatography analysis conditions were as follows: <HPLC> Detector: UV absorption photometer (measurement wavelength: 264 nm) Column: A stainless steel tube with an inner diameter of 3.0 mm and a length of 150 mm packed with octadecylsilylated silica gel for liquid chromatography with a particle size of 2.7 μm Column temperature: A constant temperature of around 30°C Flow rate: 0.5 mL / min Area measurement range: 6 minutes after sample injection Mobile phase: 25 mM ammonium acetate solution (pH 5.0) / acetonitrile mixture (13:12)

[0064] The dissolution rates of the self-emulsifying compositions 1 to 84 at pH 2.4 or pH 6.4 are shown in Tables 9 to 15. Furthermore, the AUC values ​​(Tube method AUC) of the curves obtained by plotting the time (0 to 2.25 hours) on the horizontal axis and the dissolution rate on the vertical axis for the self-emulsifying compositions 1 to 38 are also shown. 0-2.25 ) and its logarithm (Tube method Log AUC 0-2.25 ) are shown in Tables 9 to 12. Furthermore, the dissolution rates of PEG solution 2, PEG solution 3, and MC solution 2 at pH 2.4 and pH 6.4, as well as the AUC values ​​of the curves obtained by plotting time (0 to 2.25 hours) on the horizontal axis and dissolution rate on the vertical axis (Tube method AUC 0-2.25 ) and its logarithm (Tube method Log AUC 0-2.25 ) are shown in Table 16.

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] (Evaluation 1-2) Dissolution test: Tube method The above dissolution test was also carried out on Self-emulsifying Compositions 85 to 87, a Self-emulsifying composition prepared in the same manner as Self-emulsifying Composition 30 except that it contained 10% by mass of the active ingredient, 11% by mass of Capryol 90, 77.2% by mass of Kolliphor EL, and 1.8% by mass of Ethanol (hereinafter referred to as Self-emulsifying Composition 88), and MC Solution 1 and MC Solution 3 prepared in Production Example 2, to measure the dissolution rates and obtain AUC values ​​(Tube method AUC 0-2.25 ) and its logarithm (Tube method Log AUC 0-2.25 The results are shown in Table 17.

[0074]

[0075] (Evaluation 2-1) Plasma Concentration Evaluation 1 by PO / PK Test Using Rats. Self-emulsifying Compositions 85-87 were each orally administered to three male rats (Crl:CD(SD)) under fasting conditions, and the time course of the active metabolite plasma concentration of the drug substance was evaluated. The fasting conditions were at least 15 hours prior to administration. Each animal received a dose of the self-emulsifying composition equivalent to 3 mg / kg of the drug substance. Blood samples were collected from the subclavian vein at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration, and plasma was separated by centrifugation. After deproteinization with acetonitrile, the plasma concentrations of the active metabolites were measured by LC-MS / MS (API4000, AB SCIEX). Control animals received PEG Solution 1 or MC Solution 1 prepared in Preparation Example 2. The Tmax, Cmax and AUC of the active metabolite concentrations in plasma obtained are shown in Table 18.

[0076]

[0077] (Evaluation 2-2) Plasma Concentration Evaluation 2 by PO / PK Test Using Rats The time course of the total concentration of the drug substance and its active metabolite in plasma was evaluated in the same manner as in Evaluation 2-1, except that each animal was administered self-emulsifying composition 28 or 29 at a dose of 100 mg / kg or 300 mg / kg as the drug substance. Test animals administered PEG solution 3 prepared in Production Example 2 served as a control group. Table 19 shows the Cmax and AUC of the drug substance and active metabolite concentrations in plasma obtained at a dose of 100 mg / kg. Table 20 shows the Cmax and AUC of the drug substance and active metabolite concentrations in plasma obtained at a dose of 300 mg / kg.

[0078]

[0079]

[0080] (Evaluation 3) Plasma Concentration Evaluation by PO / PK Test Using Dogs. Self-emulsifying Composition 28 and Self-emulsifying Composition 88 prepared in Production Example 1 were orally administered to three male beagle dogs (10-15 months old) under fasting conditions, and the time course of plasma concentrations of the drug substance and active metabolites was evaluated. Fasting was required for at least 16 hours prior to administration. Each animal received a gelatin capsule filled with the self-emulsifying composition at a dose of 100 mg / kg of drug substance. Blood samples were collected from the cephalic vein at 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 24 hours after administration, and plasma was separated and processed. The total concentrations of the drug substance and active metabolites in plasma were measured by LC-MS / MS (API4000, AB SCIEX). A control group of test animals received PEG solution 3 prepared in Production Example 2. The Tmax, Cmax and AUC of the obtained plasma concentrations of the drug substance and active metabolite are shown in Table 21.

[0081]

[0082] (Evaluation 4) Correlation between the Tube method and PO / PK test The logarithmic value of the AUC of the Tube method obtained in Evaluation 1 (Tube method Log AUC 0-2.25 The logarithmic value of AUC (rat PO / PK Log AUC) of plasma concentration obtained in Evaluation 2 is plotted on the horizontal axis and the logarithmic value of AUC (rat PO / PK Log AUC) of plasma concentration obtained in Evaluation 2 is plotted on the vertical axis, and the results are shown in Figure 1. The logarithmic value of AUC (Tube method Log AUC) obtained in Evaluation 1 is also plotted on the vertical axis. 0-2.25 The results are shown in Figure 2 and Figure 3. The correlation coefficients in Figures 1 to 3 are shown in Table 22. 0-2.25 There is a strong positive correlation between the AUC of the PO / PK assay and that of the Tube method. 0-2.25 There is a positive correlation between the AUC of the tube method and the dissolution rates at pH 2.4 and pH 6.4. 0-2.25 Alternatively, the pharmacokinetics (AUC) in in vivo evaluation can be estimated based on the results of the dissolution rate at pH 2.4 or pH 6.4.

[0083]

[0084] The self-emulsifying composition of the present disclosure can improve the absorbability of the sulfonamide derivative represented by formula (1) after oral administration.

Claims

1. The following formula (1): A self-emulsifying composition comprising a sulfonamide derivative represented by the formula:

2. The self-emulsifying composition of claim 1, wherein the at least two solubilizing agents comprise at least one surfactant and at least one co-surfactant.

3. The self-emulsifying composition of claim 1, wherein the solubilizing agent comprises at least two selected from cyclodextrin or a derivative thereof, bile acid or a derivative thereof, a fatty alcohol, a fatty acid or a derivative thereof, and a tocol derivative.

4. The self-emulsifying composition of claim 2, wherein the surfactant comprises at least one selected from the group consisting of polyglyceryl-2 dioleate, polyglyceryl-3 dioleate, polyglyceryl-10 trioleate, propylene glycol monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate, glyceryl monolaurate, glyceryl dilaurate, and glyceryl monolinoleate.

5. The co-surfactant is selected from the group consisting of polyoxyl 40 castor oil, polyoxyl 35 castor oil, 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, caprylic / capric PEG-8 glycerides, lauroyl polyoxyl-32 glycerides, linoleoyl polyoxyl-6 glycerides, oleoyl polyoxyl-6 glycerides, stearoyl polyoxyl-32 glycerides, oleoyl polyoxyl-6 glycerides, ole ... The self-emulsifying composition of claim 2, comprising at least one selected from the group consisting of lyoxyl-32 glyceride, caprylic / capric PEG-6 glyceride, polyglyceryl-10 monooleate, polyglyceryl-10 laurate, polyglyceryl-15 hydroxystearate, alpha-tocopherol PEG 400 succinate, alpha-tocopherol PEG 1000 succinate, dl-alpha-tocopherol PEG 1000 succinate, and d-alpha-tocopherol PEG 1000 succinate.

6. A self-emulsifying composition according to any one of claims 2, 4 and 5, wherein the content of the surfactant is 0.1 times or more the mass % of the sulfonamide derivative represented by formula (1) or its pharma- ceutical acceptable salt, and the content of the auxiliary surfactant is 10 times or less the mass % of the sulfonamide derivative represented by formula (1) or its pharma-ceutical acceptable salt.

7. A self-emulsifying composition according to any one of claims 2, 4 and 5, wherein the ratio of said surfactant to said co-surfactant is from 1:1 to 8:

1.

8. A self-emulsifying composition according to claim 2 or claim 4, wherein the surfactant comprises propylene glycol monocaprylate.

9. The self-emulsifying composition of claim 2 or claim 5, wherein the co-surfactant comprises polyoxyl 40 castor oil, polyoxyl 35 castor oil, or polyoxyethylene castor oil.

10. The self-emulsifying composition of claim 1 or claim 2, further comprising a co-solvent.

11. A self-emulsifying preparation comprising the self-emulsifying composition according to claim 1 or 2, in a dosage form suitable for oral administration.

12. The self-emulsifying preparation according to claim 11, wherein the dosage form is a capsule.