Composition containing peptide compounds and surfactants

Abstract

The present invention provides a composition w comprising a peptide compound and a surfactant, wherein the membrane permeability and / or absorption of the peptide compound is enhanced. [Solution] A composition containing the following components (1) and (2): (1) A peptide compound selected from the group consisting of (i), (ii), and (iii) below; (i) A peptide compound containing one or more N-substituted amino acid residues, (ii) Peptide compounds having a ClogP of 4 or more and 25 or less, (iii) Peptide compounds having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm, (2) A surfactant selected from the group consisting of (iv) and (v) below; (iv) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms, and (v) A surfactant having a carnitine residue.

Description

[Technical Field]

[0001] The present invention relates to a composition comprising a peptide compound and a surfactant. [Background technology]

[0002] In recent years, drug discovery technologies that enable the development of drugs targeting tough targets, such as protein-protein interaction inhibitors, agonists, and molecular chaperones, using medium-sized molecules (e.g., molecular weights of 500-2000 g / mol), have attracted considerable attention.

[0003] Generally, compounds with a molecular weight of 500 g / mol or more are considered to have low membrane permeability and absorption issues. Peptide compounds, which are an example of medium-molecule compounds, are also subject to these conditions. Efforts to improve the membrane permeability of peptide compounds have been made to create peptide compounds containing N-substituted amino acid residues (e.g., N-methyl amino acid residues) as constituent components, and peptide compounds containing cyclic structures (for example, Patent Document 1). Furthermore, efforts have been made to improve absorption by combining peptide compounds with surfactants. For example, Patent Document 2 discloses a completed pharmaceutical product suitable for oral delivery, comprising a physiologically active peptide agent, at least one pharmaceutically acceptable pH lowering agent, and at least one absorption enhancer effective in increasing the bioavailability of the activator. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] International Publication No. 2013 / 100132 [Patent Document 2] Special Publication No. 2009-518437 [Overview of the project] [Problems that the invention aims to solve]

[0005] Methods for improving absorption by combining peptide compounds with surfactants such as lauroyl carnitine, as disclosed in Patent Document 2, do not require altering the structure of the peptide compound itself, thus avoiding any impact on the function of the peptide compound (e.g., its ability to bind to target proteins). On the other hand, there are no known examples of improving absorption by combining peptide compounds and surfactants as described in (1) below.

[0006] The present invention aims to provide a composition comprising a peptide compound and a surfactant, wherein the membrane permeability and / or absorption of the peptide compound is enhanced. [Means for solving the problem]

[0007] This invention relates, for example, to the following inventions. [1] A composition containing the following components (1) and (2): (1) A peptide compound selected from the group consisting of (i), (ii), and (iii) below; (i) A peptide compound containing one or more N-substituted amino acid residues, (ii) Peptide compounds having a ClogP of 4 or more and 25 or less, (iii) Peptide compounds having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm, (2) A surfactant selected from the group consisting of (iv) and (v) below; (iv) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms, and (v) A surfactant having a carnitine residue. [2] (3) The composition according to [1], further comprising a solubility improving agent. [3] The composition according to [2], wherein the content of the solubility improving agent in 100% by volume of the liquid component contained in the composition is 0.05% by volume or more and 50% by volume or less. [4] The composition according to [2], wherein the content of the solubility improving agent based on 100% by volume of the liquid component contained in the composition is 0.3% by volume or more and 30% by volume or less, preferably 0.5% by volume or more and 15% by volume or less, and more preferably 0.8% by volume or more and 10% by volume or less. [5] The composition according to any one of [2] to [4], wherein the solubility improving agent comprises a polyoxyethylene structure. [6] The composition according to [5], wherein the average number of added moles of ethylene oxide in the solubility improving agent is 2 or more and 100 or less. [7] The composition according to any one of [2] to [6], wherein the solubility improving agent is polyoxyethylene castor oil or polyoxyethylene sorbitan fatty acid ester. [8] The composition according to any one of [1] to [7], comprising 0.05 parts by mass or more and 300 parts by mass or less of the surfactant relative to 1 part by mass of the peptide compound. [9] The composition according to any one of [1] to [7], comprising 0.075 parts by mass or more and 80 parts by mass or less of the surfactant, preferably 0.1 parts by mass or more and 60 parts by mass or less, more preferably 0.2 parts by mass or more and 40 parts by mass or less, and still more preferably 0.3 parts by mass or more and 30 parts by mass or less, relative to 1 part by mass of the peptide compound.

[10] The composition according to any one of [1] to [9], wherein the substituent on the nitrogen atom of the N-substituted amino acid residue is a C1-C6 alkyl group.

[11] The composition according to

[10] , wherein the substituent on the nitrogen atom of the N-substituted amino acid residue is at least one selected from the group consisting of a methyl group and an ethyl group.

[12] The composition according to

[10] , wherein the substituent on the nitrogen atom of the N-substituted amino acid residue is a methyl group.

[13] The composition according to any one of [1] to

[12] , wherein the peptide compound is a cyclic peptide compound.

[14] The composition according to

[13] , wherein the number of amino acid residues constituting the cyclic portion of the cyclic peptide compound is 5 or more and 15 or less.

[15] The composition according to

[13] , wherein the number of amino acid residues constituting the cyclic portion of the cyclic peptide compound is 6 or more and 14 or less, preferably 7 or more and 14 or less, more preferably 8 or more and 12 or less, and even more preferably 9 or more and 11 or less.

[16] The composition according to any one of [1] to

[15] , wherein the molecular weight of the peptide compound is 5000 g / mol or less.

[17] The composition according to any one of [1] to

[15] , wherein the molecular weight of the peptide compound is 2000 g / mol or less.

[18] The composition according to any one of [1] to

[17] , wherein the molecular weight of the peptide compound is 500 g / mol or more.

[19] The composition according to any one of [1] to

[17] , wherein the molecular weight of the peptide compound is 1000 g / mol or more, preferably 1100 g / mol or more, and more preferably 1200 g / mol or more.

[20] The composition according to any one of [1] to

[19] , wherein the surfactant is represented by any one of the following general formulas (a1) to (a3). [ka] [ka] [ka] [In general formulas (a1) to (a3), R 1 X represents a saturated or unsaturated linear alkyl group having 5 to 13 carbon atoms, which may have substituents; X represents sodium or potassium; and Y represents a group represented by the following formula (a4) or a stereoisomer thereof. [ka] [In formula (a4), [ka] This indicates a bonding action. [twenty one] The aforementioned R 1 The composition according to

[20] , wherein the alkyl group is saturated and has 7 to 13 carbon atoms in a linear alkyl group. [twenty two] The aforementioned R 1 The composition according to

[20] , wherein the alkyl group is a linear alkyl group without substituents. [twenty three] The aforementioned R 1 The composition according to

[20] , wherein the linear alkyl group has 8 to 12 carbon atoms. [twenty four] The aforementioned R 1 The composition according to

[20] , wherein the linear alkyl group has 10 to 12 carbon atoms. [twenty five] The composition according to any one of [1] to

[24] , wherein the surfactant is a medium-chain fatty acid ester, a sodium medium-chain fatty acid, or a potassium medium-chain fatty acid.

[26] The composition according to any one of [1] to

[25] , wherein the surfactant is acylcarnitine.

[27] The composition according to any one of [1] to

[26] , wherein the surfactant is lauroyl-L-carnitine.

[28] The composition according to any one of [1] to

[27] , wherein the Caco-2 Papp (cm / sec) value of the peptide compound is 1.0E-9 or greater when measured in a system containing the surfactant.

[29] The composition according to any one of [1] to

[27] , wherein the Caco-2 Papp (cm / sec) value of the peptide compound is 1.0E-7 or greater when measured in a system containing the surfactant.

[30] A pharmaceutical composition, the composition described in any of [1] to

[29] .

[31] The composition according to any one of [1] to

[30] , wherein the N-substituted amino acid residue is a non-natural N-substituted amino acid residue.

[32] The composition according to any one of [1] to

[31] , wherein the number of amino acid residues of the peptide compound is 5 or more and 30 or less.

[33] The composition according to any one of [1] to

[31] , wherein the number of amino acid residues of the peptide compound is 7 or more and 25 or less, preferably 8 or more and 15 or less, and more preferably 9 or more and 13 or less.

[34] The composition according to any one of [1] to

[33] , wherein the number of ClogP / amino acid residues of the peptide compound is 1.0 or more.

[35] The composition according to any one of [1] to

[34] , wherein the surfactant is lauroyl carnitine.

[36] The composition according to any one of [1] to

[35] , wherein the surfactant is a cationic surfactant.

[37] The composition according to any one of [1] to

[36] , wherein the surfactant is an isolated component.

[38] The composition according to any one of [1] to

[37] , wherein the Caco-2 Papp (cm / sec) value of the peptide compound measured in a system containing the surfactant is at least twice as high as the value measured in a system without the surfactant.

[39] The composition according to any one of [1] to

[37] , wherein the Caco-2 Papp (cm / sec) value of the peptide compound measured in a system containing the surfactant is 3 times or more, preferably 5 times or more, and more preferably 10 times or more, compared to the value measured in a system without the surfactant.

[40] A composition for administration, as described in any of [1] to

[39] .

[41] A composition for oral administration, as described in any of [1] to

[39] .

[42] A composition for promoting the absorption of peptide compounds, as described in any one of [1] to

[41] .

[43] The composition according to any one of [1] to

[42] , comprising two or more, preferably three or more, more preferably four or more, and even more preferably five or more N-substituted amino acids of the peptide compound.

[44] The composition according to any one of [1] to

[43] , wherein the ClogP of the peptide compound is 6 or more and 23 or less, preferably 8 or more and 21 or less, and more preferably 9 or more and 20 or less.

[45] The composition according to any one of [1] to

[44] , wherein the number of ClogP / amino acid residues is 1.0 or more and 1.8 or less, preferably 1.1 or more and 1.6 or less.

[46] The composition according to any one of [1] to

[45] , wherein the solubility of the peptide compound in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 5 mg / mL or less, preferably 2.5 mg / mL or less, and more preferably 2 mg / mL or less.

[47] The composition according to any one of [1] to

[46] , wherein the surfactant has a linear alkylene structure with 6 to 13 carbon atoms, preferably 8 to 12, more preferably 10 to 12, and more preferably 11 carbon atoms.

[48] A method for producing the composition described in [1] to

[47] , comprising the following steps (a) and (b): (a) the step of preparing the peptide compound, and (b) A step of mixing the surfactant with the peptide compound as an isolated component.

[49] Furthermore, the manufacturing method described in

[48] includes the following step (c): (c) A step of mixing the solubility improving agent with the peptide compound.

[0008] The compositions described in [1] above include compositions of the following embodiments. [1-1] Compositions containing the following components; (1) A peptide compound containing one or more N-substituted amino acid residues, and (2) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms. [1-2] The composition according to [1-1], wherein the ClogP of the peptide compound is 4 or more and 25 or less. [1-3] The composition according to [1-1] or [1-2], wherein the solubility of the peptide compound in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 10 mg / mL or less. [1-4] The composition according to any one of [1-1] to [1-3], wherein the surfactant has a carnitine residue. [2-1] Compositions containing the following components; (1) Peptide compounds having a ClogP of 4 or more and 25 or less, and (2) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms. [2-2] The composition according to [2-1], comprising one or more N-substituted amino acid residues of the peptide compound. [2-3] The composition according to [2-1] or [2-2], wherein the solubility of the peptide compound in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 10 mg / mL or less. [2-4] The composition according to any one of [2-1] to [2-3], wherein the surfactant has a carnitine residue. [3-1] Compositions containing the following components; (1) A peptide compound having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm, and (2) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms. [3-2] The composition according to [3-1], comprising one or more N-substituted amino acid residues of the peptide compound. [3-3] The composition according to [3-1] or [3-2], wherein the ClogP of the peptide compound is 4 or more and 25 or less. [3-4] The composition according to any one of [3-1] to [3-3], wherein the surfactant has a carnitine residue. [4-1] Compositions containing the following components; (1) A peptide compound containing one or more N-substituted amino acid residues, and (2) A surfactant having a carnitine residue. [4-2] The composition according to [4-1], wherein the ClogP of the peptide compound is 4 or more and 25 or less. [4-3] The composition according to [4-1] or [4-2], wherein the solubility of the peptide compound in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 10 mg / mL or less. [4-4] The composition according to any one of [4-1] to [4-3], wherein the surfactant has a linear alkylene structure and the number of carbon atoms contained in the alkylene structure is 5 to 13. [5-1] Compositions containing the following components; (1) Peptide compounds having a ClogP of 4 or more and 25 or less, and (2) A surfactant having a carnitine residue. [5-2] The composition according to [5-1], comprising one or more N-substituted amino acid residues of the peptide compound. [5-3] The composition according to [5-1] or [5-2], wherein the solubility of the peptide compound in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 10 mg / mL or less. [5-4] The composition according to any one of [5-1] to [5-3], wherein the surfactant has a linear alkylene structure and the number of carbon atoms contained in the alkylene structure is 5 to 13. [6-1] Compositions containing the following components; (1) A peptide compound having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm, and (2) A surfactant having a carnitine residue. [6-2] The composition according to [6-1], comprising one or more N-substituted amino acid residues of the peptide compound. [6-3] The composition according to [6-1] or [6-2], wherein the ClogP of the peptide compound is 4 or more and 25 or less. [6-4] The composition according to any one of [6-1] to [6-3], wherein the surfactant has a linear alkylene structure and the number of carbon atoms contained in the alkylene structure is 5 to 13. [Effects of the Invention]

[0009] According to the present invention, it is possible to provide a composition containing a peptide compound and a surfactant, in which the membrane permeability and absorption of the peptide compound are enhanced. [Brief explanation of the drawing]

[0010] [Figure 1] This graph shows the blood concentration profiles of each formulation of Compound 1 (rats, 30 mg / kg). [Figure 2] This graph shows the blood concentration profiles of each formulation of compound 2 (rats, 30 mg / kg). [Figure 3] This graph shows the blood concentration profiles of each formulation of compound 3 (rats, 30 mg / kg). [Modes for carrying out the invention]

[0011] The embodiments for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.

[0012] In this specification, “one or more” means one or more numbers. When “one or more” is used in a context relating to substituents of a group, the term means a number from one up to the maximum number of substituents permitted by that group. Specifically, “one or more” could be, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or greater numbers.

[0013] In this specification, the range symbol "~" includes the values ​​at both ends of the range; for example, "A~B" means a range where A is greater than or equal to B and B is less than or equal to B.

[0014] In this specification, the term "approximately" when used in combination with a number means a range of +10% and -10% of that number.

[0015] In this invention, the meaning of the terms "and / or" includes any combination in which "and" and "or" are appropriately combined. Specifically, for example, "A, B and / or C" includes the following seven variations: (i) A, (ii) B, (iii) C, (iv) A and B, (v) A and C, (vi) B and C, (vii) A, B and C.

[0016] The composition according to this embodiment comprises the following components (1) and (2). (1) A peptide compound selected from the group consisting of (i), (ii), and (iii) below; (i) A peptide compound containing one or more N-substituted amino acid residues, (ii) Peptide compounds having a ClogP of 4 or more and 25 or less, (iii) A peptide compound having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm. (2) A surfactant selected from the group consisting of (iv) and (v) below; (iv) A surfactant having a linear alkylene structure, wherein the alkylene structure contains 5 to 13 carbon atoms, and (v) A surfactant having a carnitine residue.

[0017] [Peptide compounds] In this specification, "peptide compound" is not particularly limited as long as it is a peptide compound in which amino acid residues are linked by amide bonds or ester bonds. Preferably, the peptide compound has two or more amino acid residues linked by amide bonds. In this case, it may have ester bonds in part of the main chain, such as a depsipeptide. There are no particular restrictions on the number of amino acid residues in a peptide compound, but it is preferably 5 or more, more preferably 7 or more, even more preferably 8 or more, and even more preferably 9 or more. The number of amino acid residues in a peptide compound is also preferably 30 or less, more preferably 25 or less, even more preferably 15 or less, and even more preferably 13 or less. For example, the number of amino acid residues in a peptide compound may be 5 to 30, 7 to 25, 8 to 15, and 9 to 13. The peptide compound may have a branched structure.

[0018] All terms are used in the sense commonly understood within their respective technical fields. The meanings of each term are, but are not limited to, those exemplified below. In this specification, "amino acid" includes natural amino acids and non-natural amino acids (sometimes referred to as amino acid derivatives). Furthermore, in this specification, "amino acid residue" includes natural amino acid residues and non-natural amino acid (amino acid derivative) residues.

[0019] Natural amino acids refer to glycine (Gly), alanine (Ala), serine (Ser), threonine (Thr), valine (Val), leucine (Leu), isoleucine (Ile), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), histidine (His), glutamic acid (Glu), aspartic acid (Asp), glutamine (Gln), asparagine (Asn), cysteine ​​(Cys), methionine (Met), lysine (Lys), arginine (Arg), and proline (Pro).

[0020] Non-natural amino acids (amino acid derivatives) are not particularly limited, but examples include β-amino acids, D-type amino acids, N-substituted amino acids (excluding Pro), α,α-disubstituted amino acids, amino acids with side chains different from natural amino acids, hydroxycarboxylic acids, etc. In this specification, non-natural N-substituted amino acids mean N-substituted amino acids other than Pro.

[0021] In this specification, any stereochemistry is permitted for the amino acids. There are no particular restrictions on the selection of the amino acid side chains, but they can be freely selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroaralkyl groups, cycloalkyl groups, and spiro-bonded cycloalkyl groups, in addition to hydrogen atoms. Each of these may be substituted, and these substituents are not limited; for example, one or more substituents can be freely selected independently from any substituents including halogen atoms, O atoms, S atoms, N atoms, B atoms, Si atoms, or P atoms. Examples include substituted alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, etc., or oxo, aminocarbonyl, halogen atoms, etc. An amino acid according to one embodiment may be a compound having both a carboxyl group and an amino group within the same molecule (even in this case, imino acids such as proline and hydroxyproline are also included as amino acids).

[0022] Examples of halogen-derived substituents include fluoro(-F), chloro(-Cl), bromo(-Br), and iod(-I).

[0023] Examples of substituents derived from the oxygen atom include hydroxy(-OH), oxy(-OR), carbonyl(-C(=O)-R), carboxy(-CO2H), oxycarbonyl(-C(=O)-OR), carbonyloxy(-OC(=O)-R), thiocarbonyl(-C(=O)-SR), carbonylthio(-SC(=O)-R), aminocarbonyl(-C(=O)-NHR), carbonylamino(-NH-C(=O)-R), oxycarbonylamino(-NH-C(=O)-OR), sulfonylamino(-NH-SO2-R), aminosulfonyl(-SO2-NHR), sulfamoylamino(-NH-SO2-NHR), thiocarboxy(-C(=O)-SH), and carboxylcarbonyl(-C(=O)-CO2H).

[0024] Examples of oxy (-OR) compounds include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, and aralkyloxy compounds.

[0025] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, and aralkylcarbonyl.

[0026] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and aralkyloxycarbonyl.

[0027] Examples of carbonyloxy (-OC(=O)-R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, and aralkylcarbonyloxy.

[0028] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, and aralkylthiocarbonyl.

[0029] Examples of carbonylthio (-SC(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, and aralkylcarbonylthio.

[0030] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, and aralkylaminocarbonyl. In addition to these, compounds in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0031] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0032] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and aralkyloxycarbonylamino. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl groups are also included.

[0033] Examples of sulfonylaminos (-NH-SO2-R) include alkylsulfonylaminos, cycloalkylsulfonylaminos, alkenylsulfonylaminos, alkynylsulfonylaminos, arylsulfonylaminos, heteroarylsulfonylaminos, and aralkylsulfonylaminos. In addition to these, compounds in which the H atom bonded to the N atom in -NH-SO2-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0034] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. In addition to these, compounds in which the H atom bonded to the N atom in -SO2-NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl compounds are also included.

[0035] Examples of sulfamoylamino (-NH-SO2-NHR) include alkyl sulfamoylamino, cycloalkyl sulfamoylamino, alkenyl sulfamoylamino, alkynyl sulfamoylamino, aryl sulfamoylamino, heteroaryl sulfamoylamino, and aralkyl sulfamoylamino. Furthermore, the two H atoms bonded to the N atom in -NH-SO2-NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0036] Examples of substituents derived from the sulfur atom include thiol (-SH), thio (-SR), sulfinyl (-S(=O)-R), sulfonyl (-S(O)2-R), sulfo (-SO3H), and pentafluorosulfanil (-SF5).

[0037] Examples of thio(-SR) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, and aralkylthio.

[0038] Examples of sulfinyl (-S(=O)-R) include alkyl sulfinyl, cycloalkyl sulfinyl, alkenyl sulfinyl, alkynyl sulfinyl, aryl sulfinyl, heteroaryl sulfinyl, and aralkyl sulfinyl.

[0039] Examples of sulfonyl (-S(O)2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0040] Examples of substituents derived from the N atom include azide (-N3, also called the "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R), tertiary amino (-NR(R')), amidino (-C(=NH)-NH2), substituted amidino (-C(=NR)-NR'R''), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R''), and aminocarbonylamino (-NR-CO-NR'R'').

[0041] Examples of secondary amino acids (-NH-R) include alkylaminos, cycloalkylaminos, alkenylaminos, alkynylaminos, arylaminos, heteroarylaminos, and aralkylaminos.

[0042] Examples of tertiary aminos (-NR(R')) include alkyl(aralkyl)aminos, and any amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., where any two substituents may form a ring.

[0043] Examples of substituted amidinos (-C(=NR)-NR'R'') include groups in which the three substituents R, R', and R'' on the N atom are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl(aralkyl)(aryl)amidinos.

[0044] Examples of substituted guanidinos (-NR-C(=NR''')-NR'R'') include groups in which R, R', R'', and R''' are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, as well as groups in which these groups form a ring.

[0045] Examples of aminocarbonylamino (-NR-CO-NR'R'') include groups in which R, R', and R'' are independently selected from hydrogen atoms, alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups, as well as groups in which these groups form a ring.

[0046] Examples of substituents derived from the B atom include boryl (-BR(R')) and dioxyboryl (-B(OR)(OR')). These two substituents R and R' may be groups independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, or groups in which these groups form a ring. Specifically, examples include cyclic boryl groups, and more specifically, pinacolate boryl groups, neopentanediolate boryl groups, catecholate boryl groups, and the like.

[0047] The amino group in the main chain of an amino acid may be unsubstituted (-NH2) or substituted (i.e., -NHR, where R represents, for example, an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, cycloalkyl group, etc., which may have substituents, and a carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline).

[0048] In this specification, amino acids in which the main chain amino group is substituted are referred to as "N-substituted amino acids." Preferably, "N-substituted amino acids" in this specification include N-alkyl amino acids, N-C1-C6 alkyl amino acids, N-C1-C5 alkyl amino acids, N-C1-C4 alkyl amino acids, N-C1-C3 alkyl amino acids, N-ethyl amino acids, N-methyl amino acids, and N-C7-C 14 Examples include aralkyl amino acids, N-benzyl amino acids, and N-phenethyl amino acids, but the list is not limited to these.

[0049] Specific examples of the substituent on the nitrogen atom of the N-substituted amino acid (the R of the aforementioned -NHR) in the present specification include an alkyl group (preferably a C1-C6 alkyl group, more preferably a C1-C4 alkyl group, still more preferably a C1-C3 alkyl group, even more preferably an ethyl group or a methyl group), C7-C 14 aralkyl groups, benzyl groups, phenethyl groups, and the like. As the substituent on the nitrogen atom of the N-substituted amino acid, an ethyl group or a methyl group is more preferred, and a methyl group is particularly preferred (that is, an N-methyl amino acid is particularly preferred as the N-substituted amino acid).

[0050] The term "amino acid" as used herein includes all isotopes corresponding to each thereof. An isotope of an "amino acid" is one in which at least one atom is substituted with an atom having the same atomic number (number of protons) but a different mass number (sum of the number of protons and neutrons). Examples of isotopes included in the "amino acid" of the present specification include hydrogen atom, carbon atom, nitrogen atom, oxygen atom, phosphorus atom, sulfur atom, fluorine atom, chlorine atom, etc., each of which is 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 35 S, 18 F, 36 Cl, and the like.

[0051] The peptide compound according to this embodiment may be a cyclic peptide compound. In this specification, "cyclic peptide compound" is not particularly limited as long as it is a peptide compound having a cyclic portion composed of 5 or more amino acid residues. The number of amino acid residues constituting the cyclic portion of a cyclic peptide compound is preferably 5 to 15, 6 to 15, 6 to 14, 7 to 14, 8 to 14, or 7 to 13, more preferably 7 to 12, 8 to 12, or 8 to 11, even more preferably 9 to 11, and particularly preferably 10 or 11. The cyclic portion is preferably formed via covalent bonds such as amide bonds, carbon-carbon bond formation reactions, SS bonds, thioether bonds, or triazole bonds. Cyclization may take any form, such as cyclization via carbon-nitrogen bonds like amide bonds, cyclization via carbon-oxygen bonds like ester bonds and ether bonds, cyclization via carbon-sulfur bonds like thioether bonds, cyclization via carbon-carbon bonds, or cyclization via heterocycle construction. Of these, cyclization via covalent bonds such as amide bonds and carbon-carbon bonds is preferred, and cyclization via an amide bond between a carboxyl group in the side chain and an amino group in the main chain is more preferred. The positions of the carboxyl group and amino group used in cyclization may be on the main chain or on the side chain, and are not particularly limited as long as they are in a position where cyclization is possible.

[0052] A cyclic peptide compound may have a linear portion in addition to a cyclic portion. The specific configuration of the number of amino acid residues in a cyclic peptide compound is the same as the specific configuration of the number of amino acid residues in the peptide compound described above. When a cyclic peptide compound has a linear portion, it is preferable that the total number of amino acid residues in the cyclic and linear portions fall within the same range. Furthermore, when a cyclic peptide compound has a linear portion, the number of amino acid residues constituting the cyclic portion is preferably 5 to 15, 6 to 15, 6 to 14, 7 to 14, 8 to 14, 7 to 13, more preferably 7 to 12, 8 to 11, even more preferably 9 to 11, and particularly preferably 10 or 11. The number of amino acid residues constituting the linear portion is preferably 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, and more preferably 1 to 3.

[0053] The molecular weight of the peptide compound according to this embodiment is not particularly limited, but may be, for example, 500 g / mol or more, 550 g / mol or more, 600 g / mol or more, 650 g / mol or more, 700 g / mol or more, 750 g / mol or more, 800 g / mol or more, 850 g / mol or more, 900 g / mol or more, or 950 g / mol or more, and preferably 1000 g / mol or more, 1100 g / mol or more, 1200 g / mol or more, 1300 g / mol or more, or 1400 g / mol or more. The upper limit of the molecular weight of the peptide compound according to this embodiment is not particularly limited, but preferably 5000 g / mol or less, 4000 g / mol or less, 3000 g / mol or less, 2500 g / mol or less, or 2000 g / mol or less. In this specification, molecular weight refers to the sum of the atomic weights of the atoms constituting the compound molecule (unit: "g / mol"), and is obtained by calculating the sum of the atomic weights of the atoms included in the molecular structure formula (unit: "g / mol"). In this specification, the unit of molecular weight may be omitted. The molecular weight of the peptide compound according to this embodiment can be measured by any method known in the art, preferably by liquid chromatography, and more preferably by liquid chromatography-mass spectrometry (LC / MS) as described in the examples.

[0054] The peptide compound according to this embodiment preferably has a ClogP of 4 or more and 25 or less. ClogP is a computer-calculated partition coefficient and can be determined in accordance with the principles described in the "CLOGP Reference Manual Daylight Version 4.9 (Release date: August 1, 2011, https: / / www.daylight.com / dayhtml / doc / clogp / )". One example of a method for calculating ClogP is to use Daylight Chemical Information Systems, Inc.'s Daylight Version 4.95 (Release date: August 1, 2011, ClogP algorithm version 5.4, database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html).

[0055] The ClogP of the peptide compound according to this embodiment is more preferably 24 or less, even more preferably 23 or less, even more preferably 22 or less, even more preferably 21 or less, and particularly preferably 20 or less. The lower limit of the ClogP of the peptide compound according to this embodiment is more preferably 5 or more, even more preferably 6 or more, even more preferably 7 or more, even more preferably 8 or more, and particularly preferably 10 or more. Examples of the ClogP range of the peptide compound according to this embodiment include 5 to 24, 6 to 23, 7 to 22, 8 to 21, 9 to 20, and 10 to 20, 11 to 18, and 11.2 to 16.1.

[0056] The percentage of ClogP of the peptide compound according to this embodiment relative to cyclosporine A (ClogP: 14.36) may be 174% or less, 167% or less, 160% or less, 153% or less, 146% or less, or 139% or less. It may also be 28% or more, 35% or more, 42% or more, 49% or more, 56% or more, 63% or more, or 70% or more. The percentage of ClogP of the peptide compound according to this embodiment relative to cyclosporine A (ClogP: 14.36) may be 28% or more and 174% or less, 35% or more and 174% or less, 42% or more and 167% or less, 49% or more and 160% or less, 56% or more and 153% or less, 63% or more and 146% or less, or 70% or more and 139% or less.

[0057] Therefore, the ClogP of the peptide compound according to this embodiment can be expressed as the ClogP value or as a percentage of the ClogP of cyclosporine A, and these can be converted to each other and used interchangeably. Furthermore, it is preferable that the ClogP of the peptide compound according to this embodiment is equal to or greater than the ClogP of compound 4 described in the example, which has the following structure. [ka]

[0058] The peptide compound according to this embodiment preferably has a ClogP / amino acid residue number of 1.0 or more. Here, "number of amino acid residues" refers to the total number of amino acid residues constituting the peptide compound. For example, a cyclic peptide compound consisting of a cyclic portion with 10 amino acid residues and a linear portion with 1 amino acid residue has a total of 11 amino acid residues. The ClogP / amino acid residue number is a value calculated by dividing the ClogP of the peptide compound by the number of amino acid residues contained in the peptide compound. For example, if the ClogP of the peptide compound is 14.0 and the number of amino acid residues contained in the peptide compound is 7, the ClogP / amino acid residue number of the peptide compound is calculated to be 2.0.

[0059] The ClogP / amino acid residue count of the peptide compound according to this embodiment is more preferably 1.1 or higher, and even more preferably 1.2 or higher. The upper limit of the ClogP / amino acid residue count of the peptide compound according to this embodiment is preferably 1.8 or lower, more preferably 1.7 or lower, even more preferably 1.6 or lower, and even more preferably 1.5 or lower. Examples of the range of ClogP / amino acid residue counts of the peptide compound according to this embodiment include 1.0 to 1.8, 1.0 to 1.7, 1.1 to 1.6, and 1.1 to 1.5.

[0060] The peptide compound according to this embodiment may have a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm. The solubility of the peptide compound according to this embodiment in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm may be 5 mg / mL or less, 2.5 mg / mL or less, 2.0 mg / mL or less, 1 mg / mL or less, 0.5 mg / mL or less, 0.25 mg / mL or less, 0.1 mg / mL or less, 0.05 mg / mL or less, 0.025 mg / mL or less, 0.01 mg / mL or less, 0.005 mg / mL or less, 0.0025 mg / mL or less, or 0.001 mg / mL or less. Note that "solubility" refers to the solubility under conditions of 37°C and 1 atm. Solubility can be measured by the following procedure. A lyophilized excess of compound powder is mixed with 50 mM phosphate buffer (PPB: pH 6.5), shaken (37°C, 1 atm, 1800 rpm, 22-24 hours), filtered, and the compound concentration of the filtrate is measured by LC / MS / MS. The solubility (μg / mL) is calculated from the measured compound concentration.

[0061] The peptide compound according to this embodiment is preferably a peptide compound classified as Class IV in the Biopharmaceuticals Classification System (BCS). The BCS is a guideline for predicting the gastrointestinal absorption characteristics of a drug by classifying it into four classes (Class I to Class IV) based on its solubility and absorption rate.

[0062] In BCS, solubility (D0: Dose Number) is determined with D0=1 as the boundary. When D0≦1, solubility is judged as high (high solubility), and when D0≧1, solubility is judged as low (low solubility). Absorption rate (F) in BCS a (The rate absorbed from the digestive tract) is such that 90% absorption is the threshold, F aWhen the value is ≤0.9, it is determined that the absorption rate is low (low absorption rate), and F a A value of ≥ 0.9 is considered to indicate a high absorption rate. BCS classes I to IV are defined as follows: Class I: High solubility (D0 ≤ 1) and high absorption rate (F a (≧0.9) Class II: Low solubility (D0≧1) and high absorption rate (F a (≧0.9) Class III: High solubility (D0 ≤ 1) and low absorption rate (F a ≤0.9) Class IV: Low solubility (D0≧1) and low absorption rate (F a ≤0.9)

[0063] The Caco-2 Papp (cm / sec) values ​​of the peptide compounds according to this embodiment, when measured in a system without component (2) surfactant according to this embodiment, are preferably 1.0E-5 or less, 9.0E-6 or less, 8.0E-6 or less, 7.0E-6 or less, 6.0E-6 or less, 5.0E-6 or less, 4.0E-6 or less, and 3.0E-6 or less, and more preferably 2.0E-6 or less, 1.8E-6 or less, 1.6E-6 or less, 1.4E-6 or less, 1.2E-6 or less, 1.0E-6 or less, 9.8E-7 or less, 9.6E-7 or less, 9.4E-7 or less, 9.2E-7 or less, 9.0E-7 or less, 8.8E-7 or less, 8.6E-7 or less, 8.4E-7 or less, 8.2E-7 or less, 8.0E-7 or less, 7.8E-7 or less, and 7.6E-7 or less. Lower, 7.4E-7 or less, 7.2E-7 or less, 7.0E-7 or less, 6.8E-7 or less, 6.6E-7 or less, 6.4E-7 or less, 6.2E-7 or less, 6.0E-7 or less, 5 .8E-7 or less, 5.6E-7 or less, 5.4E-7 or less, 5.2E-7 or less, 5.0E-7 or less, 4.8E-7 or less, 4.6E-7 or less, 4.4E-7 or less, 4.2E- 7 or less, 4.0E-7 or less, 3.8E-7 or less, 3.6E-7 or less, 3.4E-7 or less, 3.2E-7 or less, 3.0E-7 or less, 2.8E-7 or less, 2.6E-7 or less, 2.4E-7 or less, 2.2E-7 or less, 2.0E-7 or less, 1.8E-7 or less, 1.6E-7 or less, 1.4E-7 or less, 1.2E-7 or less, 1.0E-7 or less. Note that En (where n is a natural number) is 10 -n This means (for example, 1.0E-5 = 1.0 × 10 -5 ).

[0064] The Caco-2 Papp (cm / sec) values ​​of the peptide compounds according to this embodiment, when measured in a system containing component (2) surfactant according to this embodiment, are preferably 1.0E-9 or higher, 1.0E-8 or higher, 2.0E-8 or higher, 3.0E-8 or higher, 4.0E-8 or higher, 5.0E-8 or higher, 6.0E-8 or higher, 7.0E-8 or higher, 8.0E-8 or higher, 9.0E-8 or higher, 1.0E-7 or higher, 1.1E-7 or higher, 1.2E-7 or higher, 1.3E-7 or higher, 1.4E-7 or higher, 1.5E-7 or higher, 1.6E-7 or higher, 1.7E-7 or higher, 1.8E-7 or higher, 1.9E-7 or higher, and 2.0E-7 or higher.

[0065] Furthermore, the Caco-2 Papp (cm / sec) value of the peptide compound according to this embodiment, when measured in a system containing component (2) surfactant, is preferably 2 times or more, more preferably 3 times or more, even more preferably 5 times or more, even more preferably 10 times or more, and even more preferably 15 times or more, compared to when measured in a system without component (2) surfactant.

[0066] The Caco-2 Papp (cm / sec) value is an indicator of membrane permeability in the cell membrane and can be measured by the following method. (1) After culturing Caco-2 cells on a plate (e.g., 96-well Transwell and Falcon® 96) for 3 weeks, the composition to be evaluated and FaSSIF / HBSS buffer (pH 6.5) are added to the apical side, and HBSS buffer (pH 7.4) containing 4% BSA is added to the basal side (start of permeability test). (2) Each well is shaken at 5% CO2, 37°C, and 80 rpm. After 180 minutes, a sample is taken from the basal side, and the amount of peptide compound permeated is measured by liquid chromatography-mass spectrometry (LC / MS / MS). (3) Calculate the transmission coefficient (Caco-2 Papp (cm / sec)) from the measured transmission amount. In addition, during the above measurement, a Pgp inhibitor (e.g., Zosquidar) may be added to the FaSSIF / HBSS buffer and the HBSS buffer, respectively. Furthermore, after step (1) and before step (2) above, pre-incubation can be performed by letting each well stand for 20 to 24 hours at 5% CO2, 37°C, and 80 rpm. Furthermore, after pre-incubation, the basal solution can be removed and washed, and a new solution of the same composition can be added. A Pgp inhibitor can also be added to this solution. When performing pre-incubation, it is preferable to use a DMEM solution (pH 7.4) containing 4% BSA instead of HBSS buffer (pH 7.4). Furthermore, the concentration of the donor-side substance to be evaluated used when calculating the permeability coefficient in step (3) above can be the concentration added initially, or the concentration measured by taking a sample of the apical-side solution before starting pre-incubation or before starting shaking in step (2) above can be used. In particular, when performing pre-incubation, it is preferable to use the concentration of the apical-side solution taken before pre-incubation. Specifically, it can be measured by the method described in the examples. Thus, when measuring the Caco-2 Papp (cm / sec) of the composition according to this embodiment, the substance to be measured is the peptide compound contained in the composition.

[0067] The composition according to this embodiment includes a peptide compound as component (1). The peptide compound included in the composition according to this embodiment is at least one selected from the group consisting of (i) peptide compounds containing one or more N-substituted amino acid residues, (ii) peptide compounds having a ClogP of 4 or more and 25 or less, and (iii) peptide compounds having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm.

[0068] (i) The peptide compound containing one or more N-substituted amino acid residues according to this embodiment can be applied without limitation to the specific embodiments of the peptide compound described above, as long as it is a peptide compound containing one or more N-substituted amino acid residues.

[0069] (i) The peptide compound containing one or more N-substituted amino acid residues according to this embodiment contains one or more N-substituted amino acid residues, preferably containing at least three N-substituted amino acid residues, more preferably containing at least four N-substituted amino acid residues, and even more preferably containing at least five N-substituted amino acid residues. The N-substituted amino acid residues may be present consecutively or discontinuously in the N-substituted cyclic peptide compound.

[0070] Specific examples of peptide compounds containing one or more N-substituted amino acid residues according to this embodiment include, for example, compounds 1 to 12 described in the examples below.

[0071] In this embodiment, the peptide compound having a ClogP of 4 or more and 25 or less can be subjected to the specific embodiments of the peptide compound described above without limitation, as long as the ClogP is 4 or more and 25 or less.

[0072] In this embodiment, the peptide compound having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm can be applied without limitation to the specific embodiments of the peptide compound described above, as long as the solubility in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm is 10 mg / mL or less.

[0073] Specific examples of peptide compounds having a solubility of 10 mg / mL or less in (iii) 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm according to this embodiment include, for example, cyclosporine A.

[0074] In this embodiment, preferred examples of peptide compounds having all of the above characteristics include compounds 1 to 12 described in the following examples.

[0075] [Surfactants] The composition according to this embodiment includes a surfactant as component (2). The surfactant according to this embodiment is at least one selected from the group consisting of (iv) surfactants having a linear alkylene structure and the number of carbon atoms contained in the alkylene structure being 5 to 13, and (v) surfactants having a carnitine residue. There may be only one surfactant, or two or more surfactants may be used in combination. The specific examples of surfactants described below may also be used in the form of salts (e.g., hydrochloride salts, sodium salts).

[0076] The surfactant according to one embodiment may be a component that promotes emulsification and dispersion of peptide compounds, a component that promotes absorption via the transcellular pathway, or a component that promotes absorption via the paracellular pathway.

[0077] A surfactant according to one embodiment has a linear alkylene structure, wherein the number of carbon atoms contained in the linear alkylene structure is 5 to 13. The number of carbon atoms is preferably 6 or more, more preferably 8 or more, even more preferably 10 or more, and particularly preferably 11. The number of carbon atoms contained in the linear alkylene structure may be 6 to 13, preferably 8 to 12, more preferably 10 to 12, and particularly preferably 11.

[0078] Examples of preferred surfactants in the present invention are shown below (the numbers in parentheses indicate the number of carbon atoms in the linear alkylene structure). (a) Caproic acid (5) (b) Caprylic acid (7) (c) Capric acid (9) (d) Lauric acid (11) (e) Lauroyl carnitine (11) (f) Lauroyl-L-carnitine (11) (g) Carnitine palmitate (15)

[0079] Furthermore, the surfactant according to one embodiment is preferably a compound represented by any of the following general formulas (a1) to (a3). [ka] [ka] [ka]

[0080] In general formulas (a1) to (a3), R 1 X represents a saturated or unsaturated linear alkyl group having 5 to 13 carbon atoms, which may have substituents; X represents sodium or potassium; and Y represents a group represented by the following formula (a4) or a stereoisomer thereof. Furthermore, an unsaturated alkyl group can also be called an unsaturated hydrocarbon group.

[0081] [ka]

[0082] In general formulas (a1) to (a3), R 1 It is preferably an alkyl group having 5 to 13 carbon atoms, more preferably an alkyl group having 7 to 12 carbon atoms, even more preferably an alkyl group having 8 to 12 carbon atoms, even more preferably an alkyl group having 10 to 12 carbon atoms, and particularly preferably an alkyl group having 11 carbon atoms. It is also preferably a linear alkyl group. It is also preferably a saturated alkyl group. It is also preferably an alkyl group without substituents. In formula (a4), [ka] This indicates a bonding hand.

[0083] Furthermore, the surfactant according to one embodiment includes a medium-chain fatty acid structure. A medium-chain fatty acid refers to a fatty acid with 6 to 12 carbon atoms. The number of carbon atoms in the medium-chain fatty acid structure is more preferably 8 or more, even more preferably 10 or more, and particularly preferably 12.

[0084] Furthermore, the surfactant according to one embodiment may be a medium-chain fatty acid ester, sodium medium-chain fatty acid, or potassium medium-chain fatty acid. A medium-chain fatty acid ester is a compound in which an ester bond is formed between the carboxyl group of a medium-chain fatty acid and the hydroxyl group of a hydroxyl group-containing compound. Examples of medium-chain fatty acids, though not limited to these, include caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, and lauric acid, among which caprylic acid, capric acid, and lauric acid are more preferably exemplified, and even more preferably lauric acid. Examples of hydroxyl group-containing compounds, though not limited to these, include aliphatic alcohols, polyhydric alcohols, and hydroxyl group-containing betaines (such as carnitine, trimethylglycine, and proline betaine).

[0085] Furthermore, the surfactant according to one embodiment is preferably acylcarnitine, more preferably lauroylcarnitine or carnitine palmitate, even more preferably lauroylcarnitine, and particularly preferably lauroyl-L-carnitine.

[0086] A surfactant according to one embodiment has a carnitine residue. The surfactant having a carnitine residue may preferably be an acylcarnitine. An acylcarnitine is a compound in which an ester bond is formed between the hydroxyl group of carnitine and the carboxyl group of a carboxyl group-containing compound. Carnitine may be a D-isomer or an L-isomer. The carboxyl group-containing compound may be an organic acid, preferably a medium-chain fatty acid such as a saturated fatty acid or an unsaturated fatty acid, and more preferably a saturated fatty acid. The number of carbon atoms in the medium-chain fatty acid is preferably 6 or more, more preferably 8 or more, even more preferably 10 or more, and particularly preferably 12. The number of carbon atoms in the saturated fatty acid is preferably 6 or more, more preferably 8 or more, even more preferably 10 or more, and particularly preferably 12. Examples of saturated fatty acids in the present invention include caproic acid, caprylic acid, capric acid, and lauric acid. As the acylcarnitine in the present invention, lauroylcarnitine or carnitine palmitate is more preferred, lauroylcarnitine is even more preferred, and lauroyl-L-carnitine is particularly preferred.

[0087] Furthermore, the surfactant according to one embodiment may be anionic surfactant, cationic surfactant, amphoteric surfactant, or nonionic surfactant. It is preferably an anionic surfactant or cationic surfactant, and more preferably a cationic surfactant. Examples of anionic surfactants include carboxylates, sulfonates, and sulfate esters, with sulfonates being preferred, and sodium lauryl sulfate (sodium dodecyl sulfate) being even more preferred.

[0088] A surfactant according to one embodiment is added to the composition according to this embodiment as an isolated component.

[0089] [Solubilization improver] The composition according to this embodiment may further contain a solubility improving agent to improve the solubility of the peptide compound. Examples of components that improve the solubility of the peptide compound include various oily components, specific polymers that form ASD (Amorphous Solid Dispersion, hereinafter referred to as "ASD") with the peptide compound, and components that adjust pH. The solubility improving agent may be a single type or two or more types may be used in combination.

[0090] Preferred examples of oily components include, for example, olive oil, almond oil, coconut oil, cocoa butter, macadamia nut oil, avocado oil, safflower oil, soybean oil, linseed oil, rapeseed oil, castor oil, palm oil, high-oleic sunflower oil, high-oleic safflower oil, sunflower oil, cottonseed oil, corn oil, sesame oil, peanut oil, apricot kernel oil, kukui nut oil, grape seed oil, pistachio seed oil, sunflower oil, hazelnut oil, jojoba oil, meadowfoam oil, and raw Examples of oily components include sip oil, tricaproin, tricaprylin, tricaprin, tripalmitolein, triolein, trilinolein, trilinolein, trilinolenin, trieicosenoin, and trierucin. In addition to those listed above, oily components may include vegetable oils extracted from plants, those partially broken down by hydrolysis, or those that have been separated and purified. They may also be synthesized using synthetic methods.

[0091] As for the oily component, it is even more preferable to use a compound in which a polyoxyethylene structure is added to the aforementioned oily component as a solubility improver. The polyoxyethylene structure is -(CH2-CH2-O) nIt is represented by -. In the compound, the average number of moles of ethylene oxide added is preferably 2 or more and 100 or less, more preferably 3 or more and 80 or less, even more preferably 3 or more and 60 or less, and even more preferably 3 or more and 50 or less. Furthermore, the average number of moles of ethylene oxide added is preferably 5 or more and 40 or less, more preferably 10 or more and 40 or less, even more preferably 20 or more and 40 or less, and even more preferably 30 or more and 40 or less.

[0092] Specific examples of compounds to which a polyoxyethylene structure has been added include, for example, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester. Among these, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid ester are preferred, polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid ester are more preferred, polyoxyethylene castor oil with an average number of added moles of ethylene oxide of 30 or more and polyoxyethylene sorbitan fatty acid ester with an average number of added moles of ethylene oxide of 10 or more and 40 or less are even more preferred, and polyoxyethylene castor oil 35 and polyoxyethylene (20) sorbitan monooleate (Tween 80) are even more preferred.

[0093] Furthermore, specific polymers that form ASDs with peptide compounds include polyethylene glycol, polyvinylpyrrolidone, copovidone, polyvinyl alcohol, cellulosic polymers, and methacrylate-methacrylate copolymers. Specific examples include vinyl polymers and copolymers having at least one substituent selected from groups including hydroxyl, alkylacyloxy, and cyclic amide; vinyl copolymers having at least one hydrophilic hydroxyl-containing repeating unit and at least one hydrophobic alkyl- or aryl-containing repeating unit; polyvinyl alcohol; polyvinyl alcohol having at least a portion of non-hydrolyzable (vinyl acetate) repeating units; polyvinyl alcohol polyvinyl acetate copolymer; polyvinylpyrrolidone; copovidone; acrylate and methacrylate copolymers; polyethylene polyvinyl alcohol copolymer; polyoxyethylene-polyoxypropylene block copolymer (also called poloxamer), polyethylene glycol, hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, and hydroxyethyl Examples include cellulose, hydroxyethylcellulose acetate, hydroxyethylcellulose, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethylethylcellulose, polyvinyl butyrate phthalate, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer (preferably in a mass ratio of 1:99 to 99:1), methacrylic acid / methyl methacrylate copolymer (preferably in a mass ratio of 1:99 to 99:1), methacrylic acid copolymer, aminoalkyl methacrylic acid copolymer E, and polyvinyl acetal diethylaminoacetate.

[0094] Specific examples of pH adjusters include lactic acid, succinic acid, gluconic acid, citric acid, citric acid hydrate, trisodium citrate, phosphoric acid, potassium carbonate, sodium bicarbonate, tartaric acid, malic acid, ascorbic acid, fumaric acid, aspartic acid, glutamic acid, glutamic acid hydrochloride, malonic acid, maleic acid, meglumine, arginine, lysine, glycine, sodium carbonate, and sodium hydrogen phosphate.

[0095] [Self-emulsifying preparation] The composition according to this embodiment may also include components in which (2) a surfactant and (3) a solubility improver are pre-mixed, such as a Self Emulsifying Drug Delivery System (SEDDS).

[0096] [Composition] The composition according to this embodiment comprises at least (1) a peptide compound and (2) a surfactant. The content of components (1) and (2) in the composition according to this embodiment may be 0.05 parts by mass or more, 0.075 parts by mass or more, 0.1 parts by mass or more, 0.2 parts by mass or more, or 0.3 parts by mass or more of (2) surfactant per 1 part by mass of (1) peptide compound. Alternatively, the content of (2) surfactant may be 300 parts by mass or less, 200 parts by mass or less, 150 parts by mass or less, 100 parts by mass or less, 80 parts by mass or less, 60 parts by mass or less, 40 parts by mass or less, or 30 parts by mass or less per 1 part by mass of (1) peptide compound. Furthermore, the content of (2) surfactant per 1 part by mass of (1) peptide compound may be 0.05 parts by mass or more and 300 parts by mass or less, 0.05 parts by mass or more and 200 parts by mass or less, 0.05 parts by mass or more and 150 parts by mass or less, 0.05 parts by mass or more and 100 parts by mass or less, 0.075 parts by mass or more and 80 parts by mass or less, 0.1 parts by mass or more and 60 parts by mass or less, 0.2 parts by mass or more and 40 parts by mass or less, or 0.3 parts by mass or more and 30 parts by mass or less. Note that the above ranges are relative to the total amount if (1) peptide compound contains two or more peptide compounds. The same applies to (2) surfactant. The content of components (1) and (2) in the composition can be measured by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography-charged particle detector, or nuclear magnetic resonance (NMR).

[0097] Furthermore, if (2) the surfactant is liquid at 25°C, the content of (2) surfactant in 100% by volume of liquid components in the composition including (2) surfactant itself is preferably 0.05% by volume or more, more preferably 0.075% by volume or more, even more preferably 0.1% by volume or more, even more preferably 0.2% by volume or more, even more preferably 0.3% by volume or more, even more preferably 0.5% by volume or more, even more preferably 0.8% by volume or more, and even more preferably 1.0% by volume or more. Also, preferably 100% by volume or less, more preferably 85% by volume or less, even more preferably 50% by volume or less, even more preferably 40% by volume or less, even more preferably 30% by volume or less, even more preferably 20% by volume or less, even more preferably 15% by volume or less, and even more preferably 10% by volume or less. Also, preferably 0.05% by volume or more and 50% by volume or less, more preferably 0.3% by volume or more and 30% by volume or less, even more preferably 0.5% by volume or more and 15% by volume or less, and even more preferably 0.8% by volume or more and 10% by volume or less.

[0098] If the composition according to this embodiment contains (3) a solubility improving agent, the content of component (1) and component (3) in the composition may be 0.1 parts by mass or more, 0.2 parts by mass or more, 0.3 parts by mass or more, 0.4 parts by mass or more, 0.5 parts by mass or more, 1 part by mass or more, 3 parts by mass or more, 4 parts by mass or more, 5 parts by mass or more, 6 parts by mass or more, or 7 parts by mass or more, per 1 part by mass of the peptide compound (1). Alternatively, it may be 100 parts by mass or less, 80 parts by mass or less, 60 parts by mass or less, 40 parts by mass or less, or 20 parts by mass or less. Note that the above ranges are relative to the total amount if the peptide compound (1) contains two or more peptide compounds.

[0099] Furthermore, if (3) the solubility improving agent is a liquid at 25°C, the content of (3) the solubility improving agent in the composition, including (3) the solubility improving agent itself, in proportion to 100% by volume of the liquid components is preferably 0.05% by volume or more, more preferably 0.075% by volume or more, even more preferably 0.1% by volume or more, even more preferably 0.2% by volume or more, even more preferably 0.3% by volume or more, even more preferably 0.5% by volume or more, and even more preferably 1.0% by volume or more. Also, preferably 100% by volume or less, more preferably 85% by volume or less, even more preferably 50% by volume or less, even more preferably 40% by volume or less, even more preferably 30% by volume or less, even more preferably 20% by volume or less, even more preferably 15% by volume or less, and even more preferably 10% by volume or less.

[0100] The content of the peptide compound (1) in the composition according to this embodiment may be set appropriately depending on the type of peptide compound, the intended use of the composition, etc. The content of the peptide compound (1) in the composition according to this embodiment is not limited to these, but examples include 0.01 mg / mL to 300 mg / mL, 0.03 mg / mL to 200 mg / mL, 0.1 mg / mL to 100 mg / mL, 0.3 mg / mL to 50 mg / mL, 1 mg / mL to 25 mg / mL, and 3 mg / mL to 10 mg / mL per 1 mL of liquid component contained in the composition according to this embodiment.

[0101] The composition according to this embodiment may contain a pharmaceutically acceptable carrier. Examples of carriers include saline solution, buffered saline solution, water, isotonic aqueous buffer solution, and combinations thereof.

[0102] The composition according to this embodiment may contain other pharmaceutically acceptable components, to the extent that they do not impair the effects of the present invention. Examples of other components include stabilizers, preservatives, antioxidants, disintegrants, excipients, binders, fluidizers, and lubricants. Examples of stabilizers include phosphatidic acid, ascorbic acid, glycerin, and cetanol. Examples of preservatives include ethyl parahydroxybenzoate and propyl parahydroxybenzoate. Examples of antioxidants include butyrated hydroxytoluene, butyrated hydroxyanisole, propyl gallate, and propyl gallate. Examples of disintegrants include carmellose calcium, croscarmellose sodium, crospovidone, and low-substituted hydroxypropyl cellulose. Examples of excipients include starches such as cornstarch, lactose, glucose, and D-mannitol. Examples of binders include sucrose, gelatin, acacia powder, and methylcellulose. Examples of fluidizing and lubricating agents include light anhydrous silicic acid, hydrated silicic acid dioxide, magnesium stearate, and talc.

[0103] The composition according to this embodiment can be used as an absorption-enhancing composition for peptide compounds in order to enhance the oral absorption of peptide compounds with low membrane permeability.

[0104] Furthermore, the compositions according to this embodiment can be used as pharmaceutical compositions targeting tough targets such as protein-protein interaction inhibitors, agonists, and molecular chaperones, depending on the type of peptide compound used.

[0105] Furthermore, the compositions according to this embodiment can be used as compositions for administration to living organisms, particularly as compositions for oral administration. Target subjects for administration include mammals, specifically mice, rats, rabbits, dogs, monkeys, and humans, and the compositions can be used particularly for administration to humans. Therefore, the compositions according to the present invention can be used as pharmaceutical compositions. Furthermore, the present invention provides a method for treatment and / or prevention, comprising administering an effective amount of the composition according to the present invention to a subject requiring it.

[0106] [Method for producing the composition according to this embodiment] The composition according to this embodiment can be manufactured by a method comprising the following steps (a) and (b): (a) A step of preparing a peptide compound, and (b) A step of mixing the surfactant with the peptide compound as an isolated component. The method for producing the composition according to this embodiment may further include the following step (c): (c) A step of mixing a solubility improving agent with the peptide compound. The peptide compound, surfactant, and solubility improving agent are as disclosed herein, respectively. [Examples]

[0107] The following describes preferred specific embodiments of the present invention as examples, but the present invention is not limited thereto.

[0108] [Synthesis Example] Synthesis of Cyclic Peptide Compounds The cyclic peptide compounds 1-12 (also simply referred to as compounds 1-12) having the amino acid sequences shown in Table 1 were synthesized by the same method as described in International Publication No. 2013 / 100132, International Publication No. 2018 / 225864, or International Publication No. 2021 / 90855, and the final product was obtained as a dried product. The rightmost part in Table 1 forms the C-terminus. Explanations of the amino acid abbreviations are provided in Tables 2-1 to 2-3. Furthermore, the structural formulas of compounds 1-12 and cyclosporine A are shown in Tables 3-0 to 3-4.

[0109] [Table 1]

[0110] [Table 2-1]

[0111] [Table 2-2]

[0112] [Table 2-3]

[0113] [Table 3-0]

[0114] [Table 3-1]

[0115] [Table 3-2]

[0116] [Table 3-3]

[0117] [Table 3-4]

[0118] The more specific synthesis procedures for compounds 1-12 are shown below.

[0119] [Synthesis Example 1: Synthesis of Compound 2] Table 4 shows the measurement conditions for liquid chromatography-mass spectrometry (LC / MS). [Table 4]

[0120] Compound 2 was synthesized according to the following scheme. [ka]

[0121] (1) Synthesis of compound aa007-a Under a nitrogen atmosphere at room temperature, a solution of compound aa033-b((2S)-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]-4-oxo-4-prop-2-enoxybutanoic acid, Fmoc-MeAsp(OAl)-OH) (87.94 g, 215 mmol), prepared by the method described in International Publication No. 2021 / 090855, in dimethylformamide (DMF) (430 ml) was added to 1-hydroxybenzotriazole (HOBt) (31.9 g, 236 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI·HCl) (49.4 g, 258 mmol), and the mixture was stirred for 30 minutes. The reaction mixture was then cooled to 0°C, and morpholine (20.44 mL, 236 mmol) was added dropwise, and the mixture was stirred at 0°C for 45 minutes. Water (180 mL) was added to the reaction mixture and the mixture was stirred at room temperature for 1 hour. Another 180 mL of water was added and the mixture was stirred at room temperature for 105 minutes. The precipitated solid was filtered and dried under reduced pressure to obtain compound aa007-a (86.83 g, yield 84%). LCMS(ESI)m / z=479(M+H) + Retention time: 2.57 minutes (Analysis conditions SMDFA05long)

[0122] (2) Synthesis of compound 2-a Solution A was obtained by adding WSCI·HCl (16.83 g, 88 mmol) at room temperature to a solution of compound aa079 ((2S)-2-cyclopentyl-2-[9H-fluoren-9-ylmethoxycarbonyl(methyl)amino]acetic acid) (22.6 g, 59.6 mmol) prepared by the method described in International Publication No. 2021 / 090855 and ethyl cyano(hydroxyimino)ethyl acetate (Oxyma) (10.69 g, 75 mmol) in DMF (203 mL) and stirring for 30 minutes.

[0123] Under a nitrogen atmosphere, diazabicycloundecene (DBU) (9.45 mL, 62.7 mmol) was added dropwise to a solution of compound aa007-a (30 g, 62.7 mmol) in DMF (203 mL) at room temperature, and the mixture was stirred for 5 minutes. Pyridine hydrochloride (7.97 g, 69 mmol) was then added, and the mixture was stirred for 5 minutes. Solution A and N,N-diisopropylethylamine (DIPEA) (10.95 mL, 62.7 mmol) were added to the resulting reaction mixture, and the mixture was stirred under a nitrogen atmosphere at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate (300 mL), washed twice with hydrochloric acid (1 mol / L, 300 mL), and the resulting aqueous phase was extracted twice with ethyl acetate (300 mL). All organic phases were mixed and washed with water (300 mL), washed twice with a saturated sodium bicarbonate aqueous solution and water mixture (1:1,300 mL), and then washed sequentially with a saturated brine and water mixture (1:1,300 mL). The resulting organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Dichloromethane (DCM) (300 mL) was added to the resulting residue, and solid matter was removed by filtration. The resulting solution was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain compound 2-a (23.8 g, yield 61.5%). LCMS(ESI)m / z=640.4(M+Na) + Retention time: 0.97 minutes (Analysis conditions SQDFA05)

[0124] (3) Synthesis of compound 2-b Under a nitrogen atmosphere at room temperature, tetrakis(triphenylphosphine)palladium(0) (0.445 g, 0.385 mmol) was added to a solution of compound 2-a (23.8 g, 38.5 mmol) in DCM (77 mL), followed by the addition of phenylsilane (3.32 mL, 27 mmol), and the mixture was stirred for 30 minutes. The reaction mixture was diluted with methyl tert-butyl ether (MTBE) (240 mL) and extracted with a mixture of saturated sodium bicarbonate aqueous solution and water (1:1,240 mL). The resulting organic phase was extracted with water (50 mL). All aqueous phases were mixed, DCM (240 mL) was added, and phosphoric acid (13.44 ml, 231 mmol) was added dropwise to separate the organic phase. The aqueous phase was then extracted with DCM (240 mL). The obtained organic phase was mixed, washed with a saturated brine and water mixture (1:1,240 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain compound 2-b (21.35 g, yield 96%). LCMS(ESI)m / z=578.4(M+H) + Retention time: 0.80 minutes (Analysis conditions SQDFA05)

[0125] (4) Synthesis of compound 2-b-resin 2-chlorotrityl chloride resin (1.36 mmol / g, 46.2 g, 62.8 mmol) was placed in a reaction vessel with a filter, DCM (462 mL) was added, and the mixture was shaken at room temperature for 45 minutes. The solvent was then drained through the filter. Compound 2-b (21.35 g, 37 mmol), methanol (11.96 mL, 296 mmol), and DIPEA (30.9 mL, 177 mmol) in a DCM (323 mL) solution were added to the reaction vessel, and the mixture was shaken at room temperature for 60 minutes. The solution was then drained through the filter. Subsequently, methanol (44.85 mL, 1.1 mol) and DIPEA (30.9 mL, 177 mmol) in a DCM (323 mL) solution were added to the reaction vessel, and the mixture was shaken at room temperature for 90 minutes. The solution was then drained through the filter. DCM (323 mL) was added to the reaction vessel, and the mixture was shaken for 5 minutes. The solvent was then drained through the filter. The washing operation of this resin was repeated four more times, and the resulting resin was dried under reduced pressure to obtain compound 2-b-resin (59.1 g). The loading amount was calculated to be 0.433 mmol / g according to the resin quantification method described in International Publication No. 2013 / 100132, International Publication No. 2018 / 225864, or International Publication No. 2021 / 90855.

[0126] (5) Synthesis of compound 2-c The subsequent extensions of Fmoc-cLeu-OH, Fmoc-Pro-OH, Fmoc-Hph(4-CF3-3-Cl)-OH (compound aa132, prepared by the method described in International Publication No. 2021 / 090855), Fmoc-MeGly-OH, Fmoc-MeCha-OH, Fmoc-Aze(2)-OH, Fmoc-MeAla-OH, Fmoc-Ile-OH, and Fmoc-MeLeu-OH were carried out by Fmoc solid-phase synthesis.

[0127] (5-1) Elongation of Fmoc-cLeu-OH Compound 2-b-resin (0.433 mmol / g, 59 g, 25.5 mmol) was added to a filter-equipped reaction vessel. DCM (600 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated once more. A DBU solution in DMF (2 v / v%, 420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 10 minutes, the solution was drained from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0128] A DMF solution (180 ml) of Fmoc-cLeu-OH (35.9 g, 102 mmol) and Oxyma (9.08 g, 63.9 mmol) was mixed with a DMF solution (10 v / v%, 216 mL) of N,N'-diisopropylcarbodiimide (DIC) at room temperature. After 2 minutes, this mixture was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 50°C for 24 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times.

[0129] (5-2) Elongation of Fmoc-Pro-OH A DBU DMF solution (2v / v%, 420 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 10 minutes, the solution was drained from the frit.

[0130] DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solution was drained from the frit. Triethylamine hydrochloride (7.03 g, 51.1 mmol) solution in DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solution was drained from the frit. DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solution was drained from the frit. This resin washing step with DMF was repeated one more time.

[0131] A solution of Fmoc-Pro-OH (17.24 g, 51.1 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol) at room temperature, and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 17 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times. DCM (420 mL) was then added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step was repeated four more times. The resulting resin was dried under reduced pressure to obtain 63.1 g of resin.

[0132] (5-3) Extension of Fmoc-Hph(4-CF3-3-Cl)-OH (compound aa132) To the solid-phase reaction vessel obtained as described above, DCM (600 mL) was added and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. Next, DMF (420 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This resin washing step with DMF was repeated once more. A DBU solution in DMF (2 v / v%, 420 mL) was then added and shaken at room temperature for 10 minutes, after which the solution was drained from the frit.

[0133] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0134] A solution of Fmoc-Hph(4-CF3-3-Cl)-OH (compound aa132) (25.7 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol) at room temperature, and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 21 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times.

[0135] (5-4) Elongation of Fmoc-MeGly-OH A DBU DMF solution (2v / v%, 420 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 10 minutes, the solution was drained from the frit.

[0136] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0137] A solution of Fmoc-MeGly-OH (15.91 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol) at room temperature, and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 32 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solution was drained from the frit. This resin washing process with DMF was repeated four more times.

[0138] (5-5) Elongation of Fmoc-MeCha-OH A DBU DMF solution (2v / v%, 420 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 10 minutes, the solution was drained from the frit.

[0139] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0140] A solution of Fmoc-MeCha-OH (20.82 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol) at room temperature, and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 12 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times. DCM (420 mL) was then added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DCM was repeated four more times. The resulting resin was dried under reduced pressure to obtain 72.4 g of resin.

[0141] (5-6) Elongation of Fmoc-Aze(2)-OH To the solid-phase reaction vessel obtained as described above, DCM (600 mL) was added and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. Next, DMF (420 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This resin washing step with DMF was repeated once more. A DBU solution in DMF (2 v / v%, 420 mL) was then added and shaken at room temperature for 10 minutes, after which the solution was drained from the frit.

[0142] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0143] A solution of Fmoc-Aze(2)-OH (16.52 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol) at room temperature, and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 21 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times. DCM (420 mL) was then added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DCM was repeated four more times. The resulting resin was dried under reduced pressure to obtain 73.1 g of resin.

[0144] (5-7) Elongation of Fmoc-MeAla-OH To the solid-phase reaction vessel obtained as described above, DCM (600 mL) was added and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. Next, DMF (420 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This resin washing step with DMF was repeated once more. A DBU solution in DMF (2 v / v%, 420 mL) was then added and shaken at room temperature for 10 minutes, after which the solution was drained from the frit.

[0145] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0146] A solution of Fmoc-MeAla-OH (16.63 g, 51.1 mmol) and HOAt (4.35 g, 31.9 mmol) in DMF (240 mL) was mixed with DIC (11.54 mL, 74.1 mmol), and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 30°C for 16 hours, and the solution was drained from the frit. DMF (420 mL) was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated four more times. DCM (420 mL) was then added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DCM was repeated four more times. The resulting resin was dried under reduced pressure to obtain 76.4 g of resin.

[0147] (5-8) Elongation of Fmoc-Ile-OH To the solid-phase reaction vessel obtained as described above, DCM (600 mL) was added and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. Next, DMF (420 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This resin washing step with DMF was repeated once more. A DBU solution in DMF (2 v / v%, 420 mL) was then added and shaken at room temperature for 10 minutes, after which the solution was drained from the frit.

[0148] Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM solution of triethylamine hydrochloride (7.03 g, 51.1 mmol) to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DCM to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solution from the frit. Add 420 mL of DMF to this solid-phase reaction vessel and shake at room temperature for 5 minutes, then drain the solvent from the frit. This resin washing step with DMF was repeated one more time.

[0149] A 180 mL DMF solution of Fmoc-Ile-OH (36.1 g, 102 mmol) and HOAt (8.69 g, 63.9 mmol) was mixed with a 216 mL DMF solution of DIC (10 v / v%), and after 2 minutes, it was added to the solid-phase reaction vessel prepared as described above. This solid-phase reaction vessel was shaken at 40°C for 8 hours, then shaken at 30°C for 14 hours. After that, the solution was drained from the frit. 420 mL of DMF was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DMF was repeated three more times. 420 mL of DCM was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This resin washing step with DCM was repeated one more time. Finally, 420 mL of toluene was added to this solid-phase reaction vessel, and after shaking at room temperature for 5 minutes, the solvent was drained from the frit. This toluene-based resin cleaning process was repeated one more time.

[0150] (5-9) Elongation of Fmoc-MeLeu-OH A toluene solution of DBU (2v / v%, 420 mL) was added to the solid-phase reaction vessel obtained as described above, and after shaking at room temperature for 10 minutes, the solution was drained from the frit.

[0151] Toluene (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solvent was drained from the frit. This toluene washing step for the resin was repeated one more time. Then, DCM (420 mL) was added to this solid-phase reaction vessel, and after shaking for 5 minutes at room temperature, the solvent was drained from the frit. This DCM washing step for the resin was repeated one more time. Herein, Fmoc-MeLeu-OH (37.6 g, 102 mmol), [ethylcyano(hydroxyimino)acetato-O 253.9 g, 102 mmol of tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxym) and 26.8 mL, 153 mmol of DIPEA were added to a 300 mL solution of DCM and shaken at 30°C for 2 hours. The solution was then drained from the frit. 420 mL of DMF was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This washing step of the resin with DMF was repeated four more times. 420 mL of DCM was added to this solid-phase reaction vessel and shaken at room temperature for 5 minutes, after which the solvent was drained from the frit. This washing step of the resin with DCM was repeated four more times. The resulting resin was dried under reduced pressure to obtain 80.9 g of resin. 40.4 g of the obtained resin (equivalent to 13 mmol based on the amount of 2-b-resin supported) was transferred to another solid-phase reaction vessel with a filter, and the following reaction was carried out.

[0152] (6) Synthesis of compound 2-c (excision of peptide from resin) 40.4 g of the resin obtained above (equivalent to 13 mmol based on the amount of 2-b-resin supported) was added to a solid-phase reaction vessel. 300 mL of DCM was added, and the mixture was shaken at room temperature for 5 minutes. The solvent was then drained from the frit. 210 mL of DMF was added to the solid-phase reaction vessel, and the mixture was shaken at room temperature for 5 minutes. The solvent was then drained from the frit. This DMF washing step was repeated one more time. 210 mL of a DBU solution in DMF (2 v / v%) was added, and the mixture was shaken at room temperature for 10 minutes. The solution was then drained from the frit. 210 mL of DMF was added to the solid-phase reaction vessel, and the mixture was shaken at room temperature for 5 minutes. The solvent was then drained from the frit. This DMF washing step was repeated four more times. 210 mL of DCM was added to the solid-phase reaction vessel, and the mixture was shaken at room temperature for 5 minutes. The solvent was then drained from the frit. This DCM washing step was repeated four more times.

[0153] To the solid-phase reaction vessel containing the resin obtained above, a mixed solution of 2,2,2-trifluoroethanol (TFE) (270 mL), DCM (270 mL), and DIPEA (4.01 mL, 23 mmol) was added and shaken at room temperature for 2 hours. The solution was then collected from the frit. A mixed solution of TFE (150 mL) and DCM (150 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 20 minutes, after which the solution was collected from the frit. Furthermore, a mixed solution of TFE (150 mL) and DCM (150 mL) was added to this solid-phase reaction vessel and shaken at room temperature for 20 minutes, after which the solution was collected from the frit. All the collected solutions were mixed, and the solvent was removed under reduced pressure to obtain compound 2-c as the crude product (18.9 g). LCMS(ESI)m / z=1474.0(M+H) + Retention time: 0.69 minutes (Analysis conditions SQDFA05)

[0154] (7) Synthesis of Compound 2 (Peptide cyclization and purification) Compound 2-c (9.6 g) obtained as described above was dissolved in a mixture of isopropyl acetate (1246 mL) and DIPEA (1.959 mL, 11.21 mmol), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) (4 g, 9.35 mmol) was added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was then washed with a mixture of saturated ammonium chloride aqueous solution (350 mL) and water (350 mL), and further washed with saturated saline solution (700 mL). The resulting organic phase was dried over sodium sulfate, and the solvent was removed under reduced pressure to obtain a residue of approximately 8 g. The same procedure was performed on compound 2-c (9.3 g), and all the resulting residues were purified by reverse-phase silica gel column chromatography (using acetonitrile (containing 0.1% formic acid) / water (containing 0.1% formic acid) as the eluate) to obtain the crude product (8.1 g). Of the crude product obtained, 7.9 g was purified by silica gel column chromatography (DCM / methanol) to obtain compound 2 (6.9 g, 37%). The mass spectral values ​​and liquid chromatography retention times of the obtained compound 2 are shown in Table 5.

[0155] [Synthesis Example 2: Synthesis of Compound 1] Using a resin (30 g) supporting a dipeptide prepared by the same method as the synthesis of compound 2-b-resin as a starting material, compound 1 (6.53 g, 56%) was obtained by a synthesis method similar to that of compound 2. The mass spectral values ​​and liquid chromatography retention times of the obtained compound 1 are shown in Table 5.

[0156] [Synthesis Example 3: Synthesis of Compound 3] Using a resin (120g) prepared by the same method as compound 2-b-resin as a raw material, compound 3 (23g, 30.5%) was obtained by a synthesis method similar to that of compound 2. The mass spectral values ​​and liquid chromatography retention times of the obtained compound 3 are shown in Table 5.

[0157] [Synthesis Example 4: Synthesis of Compounds 4-12] Peptide elongation was performed using the Fmoc method described in International Publication No. 2013 / 100132 or International Publication No. 2018 / 225864, following the basic route below. 1) The carboxylic acid of the Asp side chain was supported on 2-chlorotrityl resin, and the peptide elongation reaction from the N-terminus of the amino acid was performed by the Fmoc method. 2) Process of cleaving peptides from 2-chlorotrityllesin, 3) Amidocyclization by condensation of the carboxylic acid of the Asp side chain, which is detached from 2-chlorotrityl resin during the cleavage process, and the amino group at the N-terminus of the peptide chain. 4) Deprotection of protecting groups of side chain functional groups contained in peptide chains. The process consists of five steps: 5) purification of the compound by preparative HPLC. Furthermore, all starting materials and reagents were obtained from commercial suppliers or synthesized using known methods. The synthesis of compounds 4 and 5 will be described in detail below. Compounds 6 to 12 were also synthesized according to the peptide synthesis method described above.

[0158] <Synthesis of (S)-3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-4-oxo-4-(pyrrolidin-1-yl)butanoic acid 2-chlorotrityl resin (Fmoc-Asp(O-Trt(2-Cl)-Resin)-pyrro)>

Chemical Formula

[0159] <Synthesis of (S)-3-(((9H-fluoren-9-yl)methoxy)carbonyl(methyl)amino)-4-oxo-4-(pyrrolidin-1-yl)butanoic acid 2-chlorotrityl resin (Fmoc-MeAsp(O-Trt(2-Cl)-Resin)-pyrro)>

Chemical Formula

[0160] <Synthesis of Compound 4>

Chemical Formula

[0161] <Synthesis of Compound 5>

Chemical Formula

[0162] [Table 5]

[0163] The molecular weights of compounds 1-12 and cyclosporine A are as follows. Compound 1:1442.2g / mol Compound 2: 1456.2g / mol Compound 3: 1478.2g / mol Compound 4: 1446.7g / mol Compound 5: 1398.2g / mol Compound 6:1467.9g / mol Compound 7: 1399.8g / mol Compound 8:1454.2g / mol Compound 9:1362.1g / mol Compound 10:1414.1g / mol Compound 11:1577.0g / mol Compound 12:1613.4g / mol Cyclosporine A: 1202.6 g / mol

[0164] Furthermore, the ClogP values ​​obtained for compounds 1-12 and cyclosporine A using Daylight Version 4.95 (Daylight Chemical Information Systems, Inc.) are as follows. Compound 1:16.1 Compound 2:15.1 Compound 3:14.9 Compound 4:11.2 Compound 5:13.8 Compound 6:13.5 Compound 7:13.7 Compound 8:15.9 Compound 9:14.2 Compound 10:13.3 Compound 11:15.1 Compound 12:14.4 Cyclosporine A: 14.36

[0165] (Evaluation Example 1) Evaluation of Caco-2 membrane permeability Caco-2 cells were cultured in 96-well transwells for 3 weeks. Permeability testing was initiated by adding 10 μM of one of compounds 1-12 and 5 mM lauroyl-L-carnitine (Sigma-Aldrich or Sinochem Japan) in FaSSIF / HBSS buffer (pH 6.5) to the apical side, and 4% BSA in HBSS buffer (pH 7.4) to the basal side. Each well was shaken at 5% CO2, 37°C, and 80 rpm. After 180 minutes, a sample from the basal side was collected, and the amount of compound permeation was measured by liquid chromatography-mass spectrometry (LC / MS / MS). The permeability coefficient (Caco-2 Papp (cm / sec)) was calculated from the permeation amount, and the results are shown in Table 6.

[0166] As a comparative example, the permeation amount was measured by the same procedure as described above, except that FaSSIF / HBSS buffer (pH 6.5) not containing 5 mM lauroyl-L-carnitine was used. Specifically, any one of Compounds 1 to 12 and FaSSIF / HBSS buffer (pH 6.5) were added to the apical side. The permeability coefficient was calculated from the measured permeation amount, and the results are shown in Table 6.

[0167] [Table 6]

[0168] (Evaluation Example 2) Solubility Evaluation Solubility evaluation was performed on Compounds 1 to 12. 50 mM phosphate buffer (PPB: Phosphate buffer, pH 6.5) was added to lyophilized excess compound powder. After shaking (37°C, 1 atm, 1800 rpm, 22 to 24 hours), the mixture was filtered, and the compound concentration in the filtrate was measured by LC / MS / MS. The measurement conditions for LC / MS / MS are shown in Table 7. The solubility (µg / mL) was calculated from the measured compound concentration. The results are shown in Table 8.

[0169] [Table 7]

[0170] [Table 8]

[0171] [Example 1] Preparation of absorption-promoting preparation (1) Compound 1, lauroyl-L-carnitine (manufactured by Sigma-Aldrich or Sinochem Japan Co., Ltd.), water for injection (manufactured by Otsuka Pharmaceutical Co., Ltd.), dimethyl sulfoxide (manufactured by Wako Pure Chemical Industries, Ltd.), and Kolliphor EL (generic name: polyoxyethylene castor oil, average number of moles of ethylene oxide added: 35) (manufactured by Sigma-Aldrich, "Kolliphor EL"; the same applies hereafter unless otherwise noted) were mixed and stirred to the composition shown in Table 9-1 to prepare absorption-enhancing preparation (1). Compound 1 was mixed after being dissolved in dimethyl sulfoxide at a concentration of 60 mg / mL. Lauroyl-L-carnitine and Kolliphor EL were added and mixed as aqueous solutions.

[0172] [Examples 2-62, Comparative Examples 1-41, and Production Examples 1-19] Preparation of absorption-enhancing formulations (2)-(62), solution formulations (1)-(41), and IV formulations (1)-(19) Absorption-enhancing formulations (2) to (62), solution formulations (1) to (41), and IV formulations (1) to (19) were prepared in the same manner as in Example 1, except that compounds 1 to 12, a surfactant having a linear alkylene structure with 5 to 13 carbon atoms in the alkylene structure (lauroyl-L-carnitine, lauroyl-L-carnitine hydrochloride, sodium caprylate, sodium caprate, palmitoyl-L-carnitine hydrochloride, or sodium lauryl sulfate), water for injection or physiological saline (manufactured by Otsuka Pharmaceutical Co., Ltd.), dimethyl sulfoxide, Cremofor EL, and Tween 80 (manufactured by Nacalai Tesque Co., Ltd.) were mixed to the compositions shown in Tables 9-1 to 9-4. Compounds 1 to 12 were mixed after being dissolved in dimethyl sulfoxide to the concentrations shown in Tables 9-1 to 9-4 (compound concentration in dimethyl sulfoxide). Furthermore, in Examples 8-48, Comparative Examples 4-38, and Production Examples 3-19, the surfactant, Cremofor EL, and Tween 80 were added and mixed in powder or undiluted form, rather than as aqueous solutions. Since Tween 80 is more easily metabolized than Cremofor EL, using Tween 80 instead of Cremofor EL makes it easier to measure a more accurate PK profile because Tween 80 is less likely to interact with the peptide compounds in this specification.

[0173] [Examples 63 and 64] Preparation of absorption enhancers (63) and (64) Compound 3 and HPMCAS (manufactured by Shin-Etsu Chemical Co., Ltd.) were added to tetrahydrofuran in the ratios of Compound 3 and HPMCAS shown in Table 9-5, and the solid concentration was 12 wt / vol%, to prepare a suspension. This suspension was spray-dried to obtain a solid dispersion. This solid dispersion was mixed with sodium lauryl sulfate (manufactured by BASF), or sodium lauryl sulfate and lauroyl-L-carnitine hydrochloride, in the ratios shown in Table 9-5 to prepare absorption enhancers (63) and (64).

[0174] [Examples 65 and 66] Preparation of absorption enhancers (65) and (66) Compound 3 was dissolved by mixing propylene glycol monocaprylate (manufactured by Nikko Chemicals), Cremofor EL (manufactured by BASF), and oleic acid (manufactured by NOF) in the ratios shown in Table 9-6. This solution was encapsulated by a conventional method to prepare absorption enhancer (65). Lauroyl-L-carnitine hydrochloride was also encapsulated by a conventional method to obtain capsules of lauroyl-L-carnitine hydrochloride. Absorption enhancer (66) was prepared for use in combination with the capsules of absorption enhancer (65) and the capsules of lauroyl-L-carnitine hydrochloride. The ratios of each component when combined are as shown in Table 9-6.

[0175] In Tables 9-1 to 9-6, (*1) indicates the content in 1 mL of solvent, and (*2) indicates the content as a percentage of 100% by volume of solvent. [Table 9-1]

[0176] [Table 9-2]

[0177] [Table 9-3]

[0178] [Table 9-4]

[0179] [Table 9-5]

[0180] [Table 9-6]

[0181] (Evaluation Example 3) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (1) prepared in Comparative Example 1 and the absorption-enhancing formulations (1) to (3) prepared in Examples 1 to 3 were evaluated in rats after oral administration. Male rats (WIST, 7 weeks old, manufactured by Nippon SLC Co., Ltd.: 3 rats per group) were orally administered either the solution formulation (1) prepared in Comparative Example 1 or one of the absorption-enhancing formulations (1) to (3) prepared in Examples 1 to 3 at a dose of 30 mg / kg of compound 1. Blood was collected over time from the jugular vein using a heparinized syringe as an anticoagulant up to 24 hours after administration. In addition, the IV formulation (1) prepared in Manufacturing Example 1 was administered intravenously at a dose of 1 mg / kg of compound 1. Blood was collected over time from the jugular vein using a heparinized syringe as an anticoagulant up to 24 hours after administration. Blood was separated into plasma by centrifugation, deproteinized with acetonitrile, and then the plasma concentration of compound 1 was measured using an LC / MS / MS instrument (XEVO TQ-XS, WATERS). The blood concentration profiles of each formulation are shown in Figure 1. Furthermore, pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using non-compartmental analysis software Phoenix WinNonlin 8.2 (Certara LP), and the results are shown in Table 10.

[0182] Pharmacokinetic parameters calculated included area under the plasma concentration-time curve (AUC; ng·h / mL), maximum plasma concentration after oral administration (Cmax; ng / mL), bioavailability (BA), and relative bioavailability (rBA). If the plasma concentration was below the lower limit of quantification, the concentration was treated as 0 ng / mL. For AUC, the area under the curve was calculated from the values ​​up to 24 hours after administration, and then converted to a value corresponding to a dose of 30 mg / kg based on the actual compound concentration in the administration solution. BA was calculated as the ratio of the AUC of the solution formulation (AUCsol) or the AUC of the absorption-enhancing formulation (AUCLC) to the AUC of the IV formulation (AUCiv) at the time of administration of the same compound (AUCsol / AUCiv or AUCLC / AUCiv). rBA was calculated as the ratio of the AUC of the absorption-enhancing formulation (AUCLC / AUCsol) to the AUC of the solution formulation (AUCsol) at the time of administration of the same compound (AUCLC / AUCsol). In compound 1, the AUC of the absorption-enhancing formulations (1) to (3) in Examples 1 to 3 was confirmed to be larger than that of the solution formulation (1) in Comparative Example 1, and an increase in Cmax was also observed (Table 10). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases where lauroyl-L-carnitine was not used.

[0183] [Table 10]

[0184] (Evaluation Example 4) Rat PK test (5 mg / kg) The pharmacokinetics of the solution formulation (2) prepared in Comparative Example 2 and the absorption-enhancing formulation (4) prepared in Example 4 were evaluated in rats after oral administration. Male rats (WIST, 7 weeks old, manufactured by Nippon SLC Co., Ltd.: 3 rats per group) were orally administered either the solution formulation (2) prepared in Comparative Example 2 or the absorption-enhancing formulation (4) prepared in Example 4 at a dose of 5 mg / kg of compound 1. Blood was collected over time from the jugular vein using a heparinized syringe for up to 24 hours after administration. The blood was separated into plasma by centrifugation, deproteinized with acetonitrile, and the plasma concentration of compound 1 was measured using an LC / MS / MS instrument (XEVO TQ-XS, WATERS). Furthermore, pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using non-compartmental analysis with the analysis software Phoenix WinNonlin 8.2 (Certara LP), and the results are shown in Table 11. As a result, it was confirmed that the AUC of all groups administered with the absorption-enhancing formulation (4) in Example 4 was greater than the AUC of the group administered with the solution formulation (2) in Comparative Example 2 (Table 11). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases where lauroyl-L-carnitine is not used.

[0185] [Table 11]

[0186] (Evaluation Example 5) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (3) prepared in Comparative Example 3 and the absorption-enhancing formulations (5) to (7) prepared in Examples 5 to 7 were evaluated in rats after oral administration, and the IV formulation (2) prepared in Manufacturing Example 2 was evaluated after intravenous administration using the same method as in Evaluation Example 3. The blood concentration profiles of each formulation are shown in Figure 2. Furthermore, the pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 3, and the results are shown in Table 12. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (5) to (7) administered in Examples 5 to 7 was larger than that of the solution formulation (3) administered in Comparative Example 3, and an increase in Cmax was also observed (Table 12). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases where lauroyl-L-carnitine was not used.

[0187] [Table 12]

[0188] (Evaluation Example 6) Rat PK test (5 mg / kg) The pharmacokinetics of the solution formulation (4) prepared in Comparative Example 4 and the absorption-enhancing formulation (8) prepared in Example 8 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 13. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (8) administration group in Example 8 was larger than that of the solution formulation (4) administration group in Comparative Example 4, and an increase in Cmax was also observed (Table 13). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0189] [Table 13]

[0190] (Evaluation Example 7) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (5) prepared in Comparative Example 5 and the absorption-enhancing formulations (9) to (11) prepared in Examples 9 to 11 were evaluated in rats after oral administration, and the IV formulation (3) prepared in Manufacturing Example 3 was evaluated after intravenous administration using the same method as in Evaluation Example 3. The blood concentration profiles of each formulation are shown in Figure 3. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 3, and the results are shown in Table 14. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (9) to (11) administered in Examples 9 to 11 was larger than that of the solution formulation (5) administered in Comparative Example 5, and an increase in Cmax was also observed (Table 14). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases where lauroyl-L-carnitine was not used.

[0191] [Table 14]

[0192] (Evaluation Example 8) Rat PK test (5 mg / kg) The pharmacokinetics of the solution formulation (6) prepared in Comparative Example 6 and the absorption-enhancing formulation (12) prepared in Example 12 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 15. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (12) administration group in Example 12 was larger than that of the solution formulation (6) administration group in Comparative Example 6, and an increase in Cmax was also observed (Table 15). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0193] [Table 15]

[0194] (Evaluation Example 9) Rat PK test (5 mg / kg) The pharmacokinetics of the solution formulation (7) prepared in Comparative Example 7 and the absorption-enhancing formulation (13) prepared in Example 13 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 16. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (13) administration group in Example 13 was larger than that of the solution formulation (7) administration group in Comparative Example 7, and an increase in Cmax was also observed (Table 16). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0195] [Table 16]

[0196] (Evaluation Example 10) Rat PK test (60 mg / kg) The pharmacokinetics of the solution formulation (8) prepared in Comparative Example 8 and the absorption-enhancing formulation (14) prepared in Example 14 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 17. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (14) administration group in Example 14 was larger than that of the solution formulation (8) administration group in Comparative Example 8, and an increase in Cmax and BA was also observed (Table 17). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0197] [Table 17]

[0198] (Evaluation Example 11) Rat PK test (5 mg / kg) The pharmacokinetics of the solution formulation (9) prepared in Comparative Example 9 and the absorption-enhancing formulation (15) prepared in Example 15 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 18. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (15) administration group in Example 15 was larger than that of the solution formulation (9) administration group in Comparative Example 9, and an increase in Cmax was also observed (Table 18). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases without lauroyl-L-carnitine.

[0199] [Table 18]

[0200] (Evaluation Example 12) Rat PK test (60 mg / kg) The pharmacokinetics of the solution formulation (10) prepared in Comparative Example 10 and the absorption-enhancing formulation (16) prepared in Example 16 in rats after oral administration were evaluated using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 19. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (16) administration group in Example 16 was larger than that of the solution formulation (10) administration group in Comparative Example 10, and an increase in Cmax and BA was also observed (Table 19). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0201] [Table 19]

[0202] (Evaluation Example 13) Monkey PK test (1 mg / kg) The pharmacokinetics of the solution formulation (11) prepared in Comparative Example 11 and the absorption-enhancing formulation (17) prepared in Example 17 in monkeys after oral administration were evaluated using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 20. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (17) administration group in Example 17 was larger than that of the solution formulation (11) administration group in Comparative Example 11, and an increase in Cmax and BA was also observed (Table 20). Furthermore, the CV (standard deviation of AUC / mean AUC), which indicates the variability of AUC among individuals, was also reduced. From this, it was confirmed that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption and suppression of absorption variability compared to cases where lauroyl-L-carnitine is not used.

[0203] [Table 20]

[0204] (Evaluation Example 14) Monkey PK test (5 mg / kg) The pharmacokinetics of the solution formulation (12) prepared in Comparative Example 12 and the absorption-enhancing formulations (18) to (19) prepared in Examples 18 to 19 were evaluated in monkeys after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 21. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (18) to (19) administered in Examples 18 to 19 was larger than that of the solution formulation (12) administered in Comparative Example 12, and an increase in Cmax and BA was also observed (Table 21). Furthermore, the CV value was also reduced. From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0205] [Table 21]

[0206] (Evaluation Example 15) Monkey PK test (1 mg / kg) The pharmacokinetics of the solution formulation (13) prepared in Comparative Example 13 and the absorption-enhancing formulation (20) prepared in Example 20 were evaluated in monkeys after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 22. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (20) administration group in Example 20 was larger than that of the solution formulation (13) administration group in Comparative Example 13, and an increase in Cmax and BA was also observed (Table 22). Furthermore, the CV value was also reduced. From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0207] [Table 22]

[0208] (Evaluation Example 16) Monkey PK test (5 mg / kg) The pharmacokinetics of the solution formulation (14) prepared in Comparative Example 14 and the absorption-enhancing formulation (21) prepared in Example 21 in monkeys after oral administration were evaluated using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 23. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (21) administration group in Example 21 was larger than that of the solution formulation (14) administration group in Comparative Example 14, and an increase in Cmax and BA was also observed (Table 23). Furthermore, the CV value was also reduced. From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0209] [Table 23]

[0210] (Evaluation Example 17) Monkey PK test (15 mg / kg) The pharmacokinetics of the solution formulation (15) prepared in Comparative Example 15 and the absorption-enhancing formulations (22)-(23) prepared in Examples 22-23 were evaluated in monkeys after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 24. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (22)-(23) administered in Examples 22-23 was larger than that of the solution formulation (15) administered in Comparative Example 15, and an increase in Cmax and BA was also observed (Table 24). Furthermore, the CV value was also reduced. From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0211] [Table 24]

[0212] (Evaluation Example 18) Monkey PK test (3 mg / kg) The pharmacokinetics of the solution formulation (16) prepared in Comparative Example 16 and the absorption-enhancing formulations (24) to (26) prepared in Examples 24 to 26 were evaluated in monkeys after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 25. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (24) to (26) administered in Examples 24 to 26 was larger than that of the solution formulation (16) administered in Comparative Example 16, and an increase in BA was also observed (Table 25). Furthermore, the CV value was also reduced. From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0213] [Table 25]

[0214] (Evaluation Example 19) Mouse PK test (3 mg / kg) The pharmacokinetics of the solution formulation (17) prepared in Comparative Example 17 and the absorption-enhancing formulation (27) prepared in Example 27 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 26. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (27) administration group in Example 27 was larger than that of the solution formulation (17) administration group in Comparative Example 17, and an increase in Cmax was also observed (Table 26). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0215] [Table 26]

[0216] (Evaluation Example 20) Mouse PK test (30 mg / kg) The pharmacokinetics of the solution formulation (18) prepared in Comparative Example 18 and the absorption-enhancing formulation (28) prepared in Example 28 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 27. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (28) administration group in Example 28 was larger than that of the solution formulation (18) administration group in Comparative Example 18, and an increase in Cmax and BA was also observed (Table 27). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0217] [Table 27]

[0218] (Evaluation Example 21) Mouse PK test (3 mg / kg) The pharmacokinetics of the solution formulation (19) prepared in Comparative Example 19 and the absorption-enhancing formulation (29) prepared in Example 29 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 28. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (29) administration group in Example 29 was larger than that of the solution formulation (19) administration group in Comparative Example 19, and an increase in Cmax was also observed (Table 28). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0219] [Table 28]

[0220] (Evaluation Example 22) Mouse PK test (30 mg / kg) The pharmacokinetics of the solution formulation (20) prepared in Comparative Example 20 and the absorption-enhancing formulation (30) prepared in Example 30 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 29. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (30) administration group in Example 30 was larger than that of the solution formulation (20) administration group in Comparative Example 20, and an increase in Cmax and BA was also observed (Table 29). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0221] [Table 29]

[0222] (Evaluation Example 23) Mouse PK test (3 mg / kg) The pharmacokinetics of the solution formulation (21) prepared in Comparative Example 21 and the absorption-enhancing formulation (31) prepared in Example 31 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 30. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (31) administration group in Example 31 was larger than that of the solution formulation (21) administration group in Comparative Example 21, and an increase in Cmax was also observed (Table 30). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0223] [Table 30]

[0224] (Evaluation Example 24) Mouse PK test (30 mg / kg) The pharmacokinetics of the solution formulation (22) prepared in Comparative Example 22 and the absorption-enhancing formulation (32) prepared in Example 32 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 31. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (32) administration group in Example 32 was larger than that of the solution formulation (22) administration group in Comparative Example 22, and an increase in Cmax and BA was also observed (Table 31). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0225] [Table 31]

[0226] (Evaluation Example 25) Mouse PK test (10 mg / kg) The pharmacokinetics of the solution formulation (23) prepared in Comparative Example 23 and the absorption-enhancing formulation (33) prepared in Example 33 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 32. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (33) administration group in Example 33 was larger than that of the solution formulation (23) administration group in Comparative Example 23, and an increase in Cmax and BA was also observed (Table 32). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0227] [Table 32]

[0228] (Evaluation Example 26) Mouse PK test (100 mg / kg) The pharmacokinetics of the solution formulation (24) prepared in Comparative Example 24 and the absorption-enhancing formulation (34) prepared in Example 34 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 33. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (34) administration group in Example 34 was larger than that of the solution formulation (24) administration group in Comparative Example 24, and increases in Cmax and BA were also observed (Table 33). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases without lauroyl-L-carnitine.

[0229] [Table 33]

[0230] (Evaluation Example 27) Mouse PK test (10 mg / kg) The pharmacokinetics of the solution formulation (25) prepared in Comparative Example 25 and the absorption-enhancing formulation (35) prepared in Example 35 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 34. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (35) administration group in Example 35 was larger than that of the solution formulation (25) administration group in Comparative Example 25, and an increase in Cmax was also observed (Table 34). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0231] [Table 34]

[0232] (Evaluation Example 28) Mouse PK test (100 mg / kg) The pharmacokinetics of the solution formulation (26) prepared in Comparative Example 26 and the absorption-enhancing formulation (36) prepared in Example 36 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 35. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (36) administration group in Example 36 was larger than that of the solution formulation (26) administration group in Comparative Example 26, and increases in Cmax and BA were also observed (Table 35). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases without lauroyl-L-carnitine.

[0233] [Table 35]

[0234] (Evaluation Example 29) Mouse PK test (5 mg / kg) The pharmacokinetics of the solution formulation (27) prepared in Comparative Example 27 and the absorption-enhancing formulation (37) prepared in Example 37 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 36. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (37) administration group in Example 37 was larger than that of the solution formulation (27) administration group in Comparative Example 27, and an increase in Cmax was also observed (Table 36). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0235] [Table 36]

[0236] (Evaluation Example 30) Mouse PK test (50 mg / kg) The pharmacokinetics of the solution formulation (28) prepared in Comparative Example 28 and the absorption-enhancing formulation (38) prepared in Example 38 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 37. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (38) administration group in Example 38 was larger than that of the solution formulation (28) administration group in Comparative Example 28, and increases in Cmax and BA were also observed (Table 37). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases without lauroyl-L-carnitine.

[0237] [Table 37]

[0238] (Evaluation Example 31) Mouse PK test (90 mg / kg) The pharmacokinetics of the solution formulation (29) prepared in Comparative Example 29 and the absorption-enhancing formulation (39) prepared in Example 39 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 38. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (39) administration group in Example 39 was larger than that of the solution formulation (29) administration group in Comparative Example 29, and increases in Cmax and BA were also observed (Table 38). This confirms that using lauroyl-L-carnitine allows low-membrane-permeable compounds to exhibit higher absorption compared to cases without lauroyl-L-carnitine.

[0239] [Table 38]

[0240] (Evaluation Example 32) Mouse PK test (3 mg / kg) The pharmacokinetics of the solution formulation (30) prepared in Comparative Example 30 and the absorption-enhancing formulation (40) prepared in Example 40 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 39. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (40) administration group in Example 40 was larger than that of the solution formulation (30) administration group in Comparative Example 30, and an increase in Cmax was also observed (Table 39). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0241] [Table 39]

[0242] (Evaluation Example 33) Mouse PK test (12 mg / kg) The pharmacokinetics of the solution formulation (31) prepared in Comparative Example 31 and the absorption-enhancing formulation (41) prepared in Example 41 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 40. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (41) administration group in Example 41 was larger than that of the solution formulation (31) administration group in Comparative Example 31, and an increase in Cmax was also observed (Table 40). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0243] [Table 40]

[0244] (Evaluation Example 34) Mouse PK test (120 mg / kg) The pharmacokinetics of the solution formulation (32) prepared in Comparative Example 32 and the absorption-enhancing formulation (42) prepared in Example 42 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 41. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (42) administration group in Example 42 was larger than that of the solution formulation (32) administration group in Comparative Example 32, and an increase in Cmax and BA was also observed (Table 41). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0245] [Table 41]

[0246] (Evaluation Example 35) Mouse PK test (12 mg / kg) The pharmacokinetics of the solution formulation (33) prepared in Comparative Example 33 and the absorption-enhancing formulation (43) prepared in Example 43 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 42. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (43) administration group in Example 43 was larger than that of the solution formulation (33) administration group in Comparative Example 33, and an increase in Cmax and BA was also observed (Table 42). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0247] [Table 42]

[0248] (Evaluation Example 36) Mouse PK test (120 mg / kg) The pharmacokinetics of the solution formulation (34) prepared in Comparative Example 34 and the absorption-enhancing formulation (44) prepared in Example 44 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 43. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (44) administration group in Example 44 was larger than that of the solution formulation (34) administration group in Comparative Example 34, and an increase in Cmax and BA was also observed (Table 43). From this, it was confirmed that using lauroyl-L-carnitine resulted in higher absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0249] [Table 43]

[0250] (Evaluation Example 37) Mouse PK test (5 mg / kg) The pharmacokinetics of the solution formulation (35) prepared in Comparative Example 35 and the absorption-enhancing formulation (45) prepared in Example 45 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 44. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (45) administration group in Example 45 was larger than that of the solution formulation (35) administration group in Comparative Example 35, and an increase in Cmax and BA was also observed (Table 44). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0251] [Table 44]

[0252] (Evaluation Example 38) Mouse PK test (50 mg / kg) The pharmacokinetics of the solution formulation (36) prepared in Comparative Example 36 and the absorption-enhancing formulation (46) prepared in Example 46 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 45. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (46) administration group in Example 46 was larger than that of the solution formulation (36) administration group in Comparative Example 36, and an increase in Cmax and BA was also observed (Table 45). From this, it was confirmed that using lauroyl-L-carnitine resulted in higher absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0253] [Table 45]

[0254] (Evaluation Example 39) Mouse PK test (8 mg / kg) The pharmacokinetics of the solution formulation (37) prepared in Comparative Example 37 and the absorption-enhancing formulation (47) prepared in Example 47 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 46. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (47) administration group in Example 47 was larger than that of the solution formulation (37) administration group in Comparative Example 37, and an increase in Cmax and BA was also observed (Table 46). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0255] [Table 46]

[0256] (Evaluation Example 40) Mouse PK test (80 mg / kg) The pharmacokinetics of the solution formulation (38) prepared in Comparative Example 38 and the absorption-enhancing formulation (48) prepared in Example 48 were evaluated in mice after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 47. As a result, it was confirmed that the AUC of the absorption-enhancing formulation (48) administration group in Example 48 was larger than that of the solution formulation (38) administration group in Comparative Example 38, and an increase in Cmax and BA was also observed (Table 47). From this, it was confirmed that using lauroyl-L-carnitine resulted in high absorption of low-membrane-permeable compounds compared to cases without lauroyl-L-carnitine.

[0257] [Table 47]

[0258] (Evaluation Example 41) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (39) prepared in Comparative Example 39 and the absorption-enhancing formulations (49) to (54) prepared in Examples 49 to 54 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 48. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (49) to (54) administered in Examples 49 to 54 was larger than that of the solution formulation (39) administered in Comparative Example 39, and an increase in Cmax was also observed (Table 48). From this, it was confirmed that using surfactants having a linear alkylene structure and containing 5 to 13 carbon atoms in the alkylene structure resulted in higher absorption compared to cases where these surfactants were not used. In particular, it was confirmed that using lauroyl-L-carnitine resulted in particularly high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0259] [Table 48]

[0260] (Evaluation Example 42) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (40) prepared in Comparative Example 40 and the absorption-enhancing formulations (55) to (60) prepared in Examples 55 to 60 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 49. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (55) to (60) administered in Examples 55 to 60 was larger than that of the solution formulation (40) administered in Comparative Example 40, and the Cmax value was equivalent or higher (Table 49). From this, it was confirmed that using surfactants having a linear alkylene structure and containing 5 to 13 carbon atoms in the alkylene structure resulted in higher absorption compared to cases where these surfactants were not used. In particular, it was confirmed that using lauroyl-L-carnitine resulted in particularly high absorption of low-membrane-permeable compounds compared to cases where lauroyl-L-carnitine was not used.

[0261] [Table 49]

[0262] (Evaluation Example 43) Rat PK test (30 mg / kg) The pharmacokinetics of the solution formulation (41) prepared in Comparative Example 41 and the absorption-enhancing formulations (61) to (62) prepared in Examples 61 to 62 were evaluated in rats after oral administration using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 50. As a result, it was confirmed that the AUC of the absorption-enhancing formulations (61) to (62) administered in Examples 61 to 62 was larger than that of the solution formulation (41) administered in Comparative Example 41, and an increase in Cmax was also observed (Table 50). From this, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting higher absorption compared to cases without lauroyl-L-carnitine.

[0263] [Table 50]

[0264] (Evaluation Example 44) Monkey PK test (3 mg / kg) The absorption-enhancing formulations (63) and (64) prepared in Examples 63 and 64 were placed in separate capsules, and their pharmacokinetics after oral administration to monkeys were evaluated using the same method as in Evaluation Example 4. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 51. As a result, sufficient AUC, Cmax, and BA were confirmed in the absorption-enhancing agent (63) administration group of Example 63. Furthermore, the AUC of the absorption-enhancing formulation (64) administration group of Example 64 was confirmed to be even larger than that of the absorption-enhancing agent (63) administration group of Example 63, and further increases in Cmax and BA were also observed (Table 51). In addition, the CV value, which indicates the variability of AUC among individual monkeys, was also reduced. From this, it was confirmed that using a surfactant having a linear alkylene structure and containing 5 to 13 carbon atoms in the alkylene structure resulted in sufficiently high absorption. Furthermore, it was confirmed that using lauroyl-L-carnitine resulted in low membrane permeability compounds exhibiting even higher absorption and suppression of absorption variability compared to cases without lauroyl-L-carnitine.

[0265] [Table 51]

[0266] (Evaluation Example 45) Monkey PK test (3 mg / kg) Two capsules containing the absorption-enhancing agent (65) prepared in Example 65 were prepared. In the evaluation of Example 65, only one capsule was orally administered to the monkeys. In the evaluation of Example 66, one capsule containing the absorption-enhancing agent (65) and one capsule containing lauroyl-L-carnitine hydrochloride (a total of two capsules) were orally administered to the monkeys simultaneously, and the pharmacokinetics after oral administration were evaluated in the same manner as in Evaluation Example 4. The ratio of each component in a total weight of 3 mg of the absorption-enhancing agent (65) and lauroyl-L-carnitine hydrochloride in the evaluation of Example 66 is shown in Table 9-6. The pharmacokinetic parameters were calculated from the obtained plasma concentration profiles using the same analysis as in Evaluation Example 4, and the results are shown in Table 52. As a result, sufficient AUC, Cmax, and BA were confirmed in the absorption-enhancing agent (65) administration group of Example 65. Furthermore, it was confirmed that the AUC of the absorption-enhancing formulation (66) administration group in Example 66 was even greater than that of the absorption-enhancing agent (65) administration group in Example 65, and further increases in Cmax and BA were also observed (Table 52). In addition, the CV value, which indicates the variability of AUC among individual molecules, was also reduced. From this, it was confirmed that using a surfactant having a linear alkylene structure and containing 5 to 13 carbon atoms in the alkylene structure resulted in sufficiently high absorption. Furthermore, it was confirmed that using lauroyl-L-carnitine resulted in low membrane-permeable compounds exhibiting even higher absorption and suppression of absorption variability compared to cases where lauroyl-L-carnitine was not used.

[0267] [Table 52]

[0268] The reason why the absorption of peptide compounds is improved by the addition of lauroyl-L-carnitine is not entirely clear, but it is presumed that the improvement in absorption is due to both the promotion of absorption via the paracellular pathway, which widens tight junctions, and the promotion of absorption via the transcellular pathway, which improves the fluidity of the cell membrane.

[0269] In other words, it has been reported that lauroyl-L-carnitine suppresses the expression of claudin protein and widens tight junctions (Drug Metab. Pharmacokinet., 26(2):162170 (2011)), and it is thought that it helps peptide compounds pass through tight junctions and be taken up into cells. Furthermore, since lauroyl-L-carnitine has the function of a surfactant, it is also thought that it extracts phospholipids, which are lipid-soluble components present in the cell membrane, making the cell membrane surface "sparse" or integrating into the phospholipid membrane, thereby making it easier for peptide compounds to pass through the cell membrane.

[0270] However, while it is known that adding lauroyl-L-carnitine to other peptides only improves bioavailability to a single-digit percentage (Pharmaceutics, 2019, 11(1), 41), as shown in this example, when lauroyl-L-carnitine is added to the peptide compound according to the present invention, its bioavailability is significantly improved by several tens of percent. This indicates that the combination of the peptide compound and the surfactant according to the present invention exhibits a particularly remarkable effect on the membrane permeability and absorption of the peptide compound. Furthermore, there is a possibility that other special mechanisms of action, not yet discovered, are at work. Similarly, since the variation in the absorption amount of the peptide compound is suppressed by the addition of lauroyl-L-carnitine, it can be seen that using the peptide compound and lauroyl-L-carnitine in combination in the present invention yields effects that are different from those of the prior art.

Claims

[Claim 1] A composition containing the following components (1) and (2): (1) At least one peptide compound selected from the group consisting of (i), (ii), and (iii) below; (i) A peptide compound containing one or more N-substituted amino acid residues, (ii) A peptide compound having a ClogP of 4 or more and 25 or less, (iii) Peptide compounds having a solubility of 10 mg / mL or less in 50 mM phosphate buffer (pH 6.5) at 37°C and 1 atm, (2) A surfactant selected from the group consisting of (iv) and (v) below; (iv) A surfactant having a linear alkylene structure, wherein the number of carbon atoms contained in the alkylene structure is 5 or more and 13 or less, and (v) A surfactant having a carnitine residue.

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