Composition containing cyclic peptide compound and surfactant

Abstract

The present invention relates to a composition comprising a compound represented by general formula (1), a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the salt, and a surfactant. (In general formula (1): R1, P1, R2, P3, P4, R5, P6, R10, P10 and P11 are C1-C6 alkyl groups or the like; r3 and P9 are hydrogen or the like; r7 is phenethyl optionally substituted by halogen or the like; r8, P8, a carbon atom to which R8 is bonded, and a nitrogen atom to which P8 is bonded together form a quaternary to seven-membered saturated heterocyclic ring; the carbon atoms to which R9 and Q9 are bonded and the carbon atoms to which R9 and Q9 are bonded together form a three-membered to eight-membered alicyclic ring; and R11 is a di-C1 to C6 alkylaminocarbonyl group or the like)

Description

Technical Field

[0001] This invention relates to compositions containing cyclic peptide compounds and surfactants, particularly cyclic peptide compounds and surfactants that selectively inhibit KRAS activity against HRAS and NRAS. Background Technology

[0002] RAS are proteins belonging to the small GTPase family, of which KRAS, NRAS, and HRAS are known. RAS are defined as activated or inactivated based on their binding state with GDP or GTP, and are activated by the exchange of GDP for GTP via GEF (guanine nucleotide exchange factor) and inactivated by the hydrolysis of GTP via GAP (GTPase activator protein) (Non-Patent Literature 1). Activated RAS induces cell proliferation, survival, and differentiation by activating various downstream signaling pathways such as the MAPK, PI3K / Akt, and RAL pathways, and constitutive activation of RAS plays a crucial role in cancer development and progression. In cancer, the RAS-RAF-MEK-ERK pathway is known to be activated due to activation of upstream RAS signaling, constitutive activation of RAS, and / or activating mutations in RAS (Non-Patent Literature 2). These activating mutations of RAS have been found in various types of cancer. G12, G13, and Q61 are known as RAS mutation hotspots, and mutations are frequently found at G12 in KRAS and Q61 in NRAS. These mutations are also known to be associated with patient prognosis (Non-Patent Literature 3).

[0003] Meanwhile, when approaching challenging targets such as inhibiting protein-protein interactions, medium-molecular-weight compounds (molecular weight of 500 to 2000 g / mol) may outperform small-molecular-weight compounds. Medium-molecular-weight compounds may also outperform antibodies because they can migrate into cells. Among bioactive medium-molecular-weight compounds, peptide drugs are high-value molecular species, and more than 40 peptide drugs are already on the market (Non-Patent Literature 4). Representative examples of these peptide drugs include cyclosporine A and polymyxin B. These peptide drugs are peptides containing several non-natural amino acids. Non-natural amino acids are amino acids not naturally encoded on mRNA, and interestingly, non-natural amino acids are contained in naturally derived cyclosporine A and polymyxin B.

[0004] Since the discovery that naturally derived peptides can be used as drugs, peptides with pharmacological activity and that can be absorbed by living organisms have attracted much attention, and peptides with a molecular weight of about 500 to 2000 g / mol have been actively studied (Non-Patent Literature 5).

[0005] Compounds with a molecular weight of 500 g / mol or higher are generally considered to have low membrane permeability and bioavailability (BA) problems. This is also true for peptide compounds, which are examples of mediator molecules. As a strategy to improve the membrane permeability of peptide compounds, peptide compounds containing N-substituted amino acid residues (e.g., N-methyl amino acid residues) as components, cyclic peptide compounds containing cyclic structures, etc., have been created (e.g., Patent Document 1). In addition, attempts have been made to combine peptide compounds with surfactants to improve BA. For example, Patent Document 2 discloses a finished pharmaceutical product suitable for oral delivery, which contains a physiologically active peptide, at least one pharmaceutically acceptable pH lowering agent, and at least one absorption enhancer that effectively improves the bioavailability of the active agent.

[0006] In this context, cyclic peptide compounds with selectivity in RAS have been reported, particularly selective KRAS inhibition of HRAS and NRAS (Patent Document 3).

[0007] Citation List

[0008] Patent documents

[0009] Patent Document 1: International Publication No. WO2013 / 100132

[0010] Patent Document 2: Japanese translation of PCT International Application Publication No. JP2009-518437

[0011] Patent Document 3: International Publication No. WO2022 / 234853

[0012] Non-patent literature

[0013] Non-patent literature 1: Nat. Rev. Drug Discov., 2014, Vol. 13, No. 11, pp. 828-851

[0014] Non-patent literature 2: Nat. Rev. Drug Discov., 2014, Vol. 13, No. 12, pp. 928-942

[0015] Non-patent literature 3: Nat. Rev. Drug Discov., 2016, Vol. 15, No. 11, pp. 771-785

[0016] Non-patent literature 4: Future Med. Chem., 2009, Vol. 1, pp. 1289-1310

[0017] Non-patent literature 5: Current Topics in Medicinal Chemistry, 2013, Vol. 13, No. 7, pp. 821-836 Summary of the Invention

[0018] Technical issues

[0019] To the best of the inventors' knowledge, there are no reports of combining cyclic peptide compounds with surfactants to enhance the BA of cyclic peptide compounds that have selective KRAS inhibitory effects on HRAS and NRAS.

[0020] The present invention aims to provide a composition comprising a cyclic peptide compound and a surfactant, the composition having enhanced membrane permeability and / or bioavailability (BA) of the cyclic peptide compound. Another objective is to provide a composition comprising a cyclic peptide compound for use in combination with a surfactant. Yet another objective is to provide a method for using a surfactant to improve the membrane permeability and / or BA of a cyclic peptide compound.

[0021] Solution to the problem

[0022] This invention relates to each of the following inventions, for example.

[0023] [A1]

[0024] A composition comprising a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and a surfactant:

[0025] [Formula 1]

[0026]

[0027] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0028] P1 is a C1 to C6 alkyl group;

[0029] R2 is a C1 to C6 alkyl group;

[0030] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0031] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0032] P4 is a C1 to C6 alkyl group;

[0033] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0034] P6 is a C1 to C6 alkyl group;

[0035] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0036] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0037] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0038] P9 is hydrogen or a C1 to C6 alkyl group;

[0039] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0040] P 10 It is a C1 to C6 alkyl group;

[0041] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0042] P 11 (C1 to C6 alkyl).

[0043] [A2]

[0044] A composition comprising a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, used in combination with a surfactant:

[0045] [Equation 2]

[0046]

[0047] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0048] P1 is a C1 to C6 alkyl group;

[0049] R2 is a C1 to C6 alkyl group;

[0050] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0051] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0052] P4 is a C1 to C6 alkyl group;

[0053] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0054] P6 is a C1 to C6 alkyl group;

[0055] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0056] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0057] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0058] P9 is hydrogen or a C1 to C6 alkyl group;

[0059] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0060] P 10 It is a C1 to C6 alkyl group;

[0061] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0062] P 11(C1 to C6 alkyl).

[0063] [A3]

[0064] According to the composition described in [A1] or [A2], wherein the surfactant is represented by any one of the following general formulas (a1) to (a3):

[0065] [Formula 3]

[0066]

[0067] [Formula 4]

[0068]

[0069] [Formula 5]

[0070]

[0071] [where R] S1 This indicates a saturated or unsaturated straight-chain hydrocarbon group having 5 or more and 13 or fewer carbon atoms, which may have substituents; X represents sodium or potassium; and Y represents a group represented by formula (a4) or a stereoisomer thereof.

[0072] [Formula 6]

[0073]

[0074] [in

[0075] [Formula 7]

[0076]

[0077] Indicates a key.

[0078] [A4]

[0079] According to the composition described in [A3], wherein the R S1 It is a straight-chain alkyl group having 7 or more and 13 or fewer carbon atoms.

[0080] [A5]

[0081] According to the composition described in [A3], wherein R S1 It is an unsubstituted straight-chain alkyl group.

[0082] [A6]

[0083] According to the composition described in [A3], wherein the R S1It is a straight-chain alkyl group having 8 or more and 12 or fewer carbon atoms.

[0084] [A7]

[0085] According to the composition described in [A3], wherein the R S1 It is a straight-chain alkyl group having 10 or more and 12 or fewer carbon atoms.

[0086] [A8]

[0087] The composition according to any one of [A1] to [A7], wherein the surfactant is a medium-chain fatty acid ester, a sodium salt of a medium-chain fatty acid, or a potassium salt of a medium-chain fatty acid.

[0088] [A9]

[0089] The composition according to any one of [A1] to [A8], wherein the surfactant is acylcarnitine.

[0090] [A10]

[0091] The composition according to [A9], wherein the acylcarnitine is lauroyl-L-carnitine.

[0092] [A11]

[0093] The composition according to any one of [A1] to [A8], wherein the surfactant is an alkyl carboxylate.

[0094] [A12]

[0095] The composition according to [A11], wherein the surfactant is octanoate.

[0096] [A13]

[0097] The composition according to [A12], wherein the surfactant is sodium octanoate.

[0098] [A14]

[0099] The composition according to any one of [A1] to [A8], wherein the surfactant is an alkyl sulfate.

[0100] [A15]

[0101] The composition according to [A14], wherein the surfactant is lauryl sulfate.

[0102] [A16]

[0103] The composition according to [A15], wherein the surfactant is sodium lauryl sulfate.

[0104] [A17]

[0105] The composition according to [A3], wherein the substituent is an N-(2-hydroxybenzoyl)amino group.

[0106] [A18]

[0107] The composition according to [A17], wherein the surfactant is N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0108] [A19]

[0109] The composition according to [A18], wherein the surfactant is sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0110] [A20]

[0111] A composition comprising a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and a surfactant selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate:

[0112] [Formula 8]

[0113]

[0114] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0115] P1 is a C1 to C6 alkyl group;

[0116] R2 is a C1 to C6 alkyl group;

[0117] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0118] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0119] P4 is a C1 to C6 alkyl group;

[0120] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0121] P6 is a C1 to C6 alkyl group;

[0122] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0123] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0124] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0125] P9 is hydrogen or a C1 to C6 alkyl group;

[0126] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0127] P 10 It is a C1 to C6 alkyl group;

[0128] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0129] P 11 (C1 to C6 alkyl).

[0130] [A21]

[0131] The composition according to any one of [A1] to [A20], wherein R1 is n-propyl.

[0132] [A22]

[0133] The composition according to any one of [A1] to [A20], wherein R1 is 2-methylpropyl.

[0134] [A23]

[0135] The composition according to any one of [A1] to [A20], wherein R1 is cyclopentylmethyl.

[0136] [A24]

[0137] The composition according to any one of [A1] to [A23], wherein P1 is methyl.

[0138] [A25]

[0139] The composition according to any one of [A1] to [A24], wherein R2 is 1-methylpropyl.

[0140] [A26]

[0141] The composition according to any one of [A1] to [A25], wherein R3 is hydrogen.

[0142] [A27]

[0143] The composition according to any one of [A1] to [A25], wherein R3, together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, forms a 5-membered saturated heterocycle.

[0144] [A28]

[0145] The composition according to any one of [A1] to [A27], wherein P3 is methyl.

[0146] [A29]

[0147] The composition according to any one of [A1] to [A27], wherein P3, together with R3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, forms a 5-membered saturated heterocycle.

[0148] [A30]

[0149] The composition according to any one of [A1] to [A27], wherein P3 is cyclopropyl.

[0150] [A31]

[0151] The composition according to any one of [A1] to [A30], wherein P4 is methyl.

[0152] [A32]

[0153] The composition according to any one of [A1] to [A31], wherein R5 is 4-trifluoromethylbenzyl.

[0154] [A33]

[0155] The composition according to any one of [A1] to [A31], wherein R5 is 4-methylbenzyl.

[0156] [A34]

[0157] The composition according to any one of [A1] to [A33], wherein P6 is methyl.

[0158] [A35]

[0159] The composition according to any one of [A1] to [A34], wherein R7 is 3-methoxy-4-trifluoromethylphenylethyl.

[0160] [A36]

[0161] The composition according to any one of [A1] to [A34], wherein R7 is 3,5-difluoro-4-trifluoromethylphenylethyl.

[0162] [A37]

[0163] The composition according to any one of [A1] to [A36], wherein R8, together with P8 and the carbon atom bonded to R8 and the nitrogen atom bonded to P8, forms a 5-membered saturated heterocycle, said 5-membered saturated heterocycle being ethoxylated.

[0164] [A38]

[0165] The composition according to any one of [A1] to [A37], wherein R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 4- or 5-membered alicyclic ring.

[0166] [A39]

[0167] The composition according to any one of [A1] to [A38], wherein R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 4-membered alicyclic ring, the 4-membered alicyclic ring being substituted with two methyl groups.

[0168] [A40]

[0169] The composition according to any one of [A1] to [A39], wherein P9 is hydrogen or methyl.

[0170] [A41]

[0171] The composition according to any one of [A1] to [A40], wherein R10 It is cyclopentyl.

[0172] [A42]

[0173] The composition according to any one of [A1] to [A41], wherein P 10 It is a methyl group.

[0174] [A43]

[0175] The composition according to any one of [A1] to [A42], wherein R 11 It is a dimethylaminocarbonyl group.

[0176] [A44]

[0177] The composition according to any one of [A1] to [A43], wherein P 11 It is a methyl group.

[0178] [A45]

[0179] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1a).

[0180] [Formula 9]

[0181]

[0182] [A46]

[0183] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1b).

[0184] [Formula 10]

[0185]

[0186] [A47]

[0187] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1c).

[0188] [Equation 11]

[0189]

[0190] [A48]

[0191] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1d).

[0192] [Equation 12]

[0193]

[0194] [A49]

[0195] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1e).

[0196] [Equation 13]

[0197]

[0198] [A50]

[0199] The composition according to any one of [A1] to [A20], wherein the compound represented by general formula (1) is a compound represented by formula (1f).

[0200] [Formula 14]

[0201]

[0202] [A51]

[0203] The composition according to any one of [A1] to [A50] comprises a pharmaceutical excipient.

[0204] [A52]

[0205] The composition according to any one of [A1] to [A51] is in the form of capsules or tablets.

[0206] [A53]

[0207] The composition according to any one of [A1] to [A52] is a pharmaceutical composition.

[0208] [A54]

[0209] The composition according to any one of [A1] to [A53], wherein the bioavailability (BA) of the compound measured in a system in the presence of the surfactant is 1.1 times or greater than the value measured in a system in the absence of the surfactant.

[0210] [A55]

[0211] The composition according to any one of [A1] to [A54], wherein the bioavailability (BA) of the compound measured in a system in the presence of the surfactant is 1.2 times or greater, 1.4 times or greater, 1.6 times or greater, 1.8 times or greater, or 2.0 times or greater than the value measured in a system in the absence of the surfactant.

[0212] [A56]

[0213] The composition according to any one of [A1] to [A55], wherein the bioavailability (BA) of the compound measured in a system in the presence of the surfactant is 2.0 times or greater than the value measured in a system in the absence of the surfactant.

[0214] [A57]

[0215] The composition according to any one of [A1] to [A56], wherein the value of Caco-2 Papp (cm / sec) of the compound measured in a system in the presence of the surfactant is 1.1 times or greater than the value measured in a system in the absence of the surfactant.

[0216] [A58]

[0217] The composition according to any one of [A1] to [A57], wherein the Caco-2 Papp (cm / sec) value of the compound measured in a system in the presence of the surfactant is 1.2 times or greater, 1.5 times or greater, 2 times or greater, 3 times or greater, or 5 times or greater than the value measured in a system in the absence of the surfactant.

[0218] [A59]

[0219] The composition according to any one of [A1] to [A58], wherein the value of Caco-2 Papp (cm / sec) of the compound measured in a system in the presence of the surfactant is twice or greater than the value measured in a system in the absence of the surfactant.

[0220] [A60]

[0221] The composition according to any one of [A1] to [A59] further comprises a solubility improver.

[0222] [A61]

[0223] According to the composition of [A60], the solubility improver is present in an amount of 0.05% or more and 50% or less, based on 100% by volume of the liquid component contained in the composition.

[0224] [A62]

[0225] According to the composition of [A60] or [A61], wherein the solubility improver is present in an amount of 0.3 vol% or more and 30 vol% or less, preferably 0.5 vol% or more and 15 vol% or less, more preferably 0.8 vol% or more and 10 vol% or less, based on 100 vol% of the liquid component contained in the composition.

[0226] [A63]

[0227] The composition according to any one of [A60] to [A62], wherein the solubility improver comprises a polyoxyethylene structure.

[0228] [A64]

[0229] The composition according to [A63] wherein the average molar number of ethylene oxide added to the solubility improver is 2 or more and 100 or less.

[0230] [A65]

[0231] The composition according to any one of [A60] to [A64], wherein the solubility improver is polyoxyethylene castor oil or polyoxyethylene sorbitan fatty acid ester.

[0232] [A66]

[0233] The composition according to any one of [A60] to [A62], wherein the solubility improver comprises a polymer that forms a solid dispersion with the compound.

[0234] [A67]

[0235] According to the composition described in [A66], the polymer forming the solid dispersion is selected from the group consisting of: polyethylene glycol, polyvinylpyrrolidone, copolyvinyl ketone, polyvinyl alcohol, cellulose-based polymers, and methacrylic acid-methacrylic acid copolymers.

[0236] [A68]

[0237] According to the composition described in [A66], the polymer forming the solid dispersion is selected from the group consisting of: polyvinyl alcohol, polyvinyl alcohol-vinyl acetate copolymer, polyvinylpyrrolidone, copovidone, copolymers of acrylates and methacrylic acid, polyethylene-polyvinyl alcohol copolymer, polyoxyethylene-polyoxypropylene block copolymer (also known as poloxamer), polyethylene glycol, hydroxypropyl methylcellulose acetate (HPMCA), hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl... Cellulose acetate, hydroxyethyl ethyl cellulose, cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methyl cellulose phthalate, hydroxymethyl cellulose ethyl phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol 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.

[0238] [A69]

[0239] The composition according to any one of [A1] to [A68], wherein the composition comprises 0.05 parts by mass or more based on 1 part by mass of the compound and 300 parts by mass or less of the surfactant.

[0240] [A70]

[0241] The composition according to any one of [A1] to [A69], wherein the composition comprises 0.075 parts by mass or more and 80 parts by mass or less, 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 further preferably 0.3 parts by mass or more and 30 parts by mass or less, based on 1 part by mass of the compound.

[0242] [A71]

[0243] The composition according to any one of [A1] to [A70] is a composition for application.

[0244] [A72]

[0245] The composition according to any one of [A1] to [A71] is a composition for oral administration.

[0246] [A73]

[0247] The composition according to any one of [A1] to [A72] is a composition for promoting the absorption of said compound.

[0248] [A74]

[0249] The composition according to [A2] wherein, based on 1 part by weight of the compound, the amount of surfactant used in combination is 0.05 parts by weight or more and 300 parts by weight or less.

[0250] [A75]

[0251] According to the composition described in [A2] or [A74], the amount of surfactant used in combination is 0.075 parts by mass or more and 80 parts by mass or less, 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 even more preferably 0.3 parts by mass or more and 30 parts by mass or less, based on 1 part by mass of the compound.

[0252] [A76]

[0253] The composition according to any one of [A1] to [A75] is a pharmaceutical composition for treating or preventing cancer.

[0254] [A77]

[0255] A method for improving the absorption of compounds represented by general formula (1),

[0256] The method comprises incorporating a compound represented by general formula (1), its pharmaceutical salt, or a pharmaceutical solvate thereof, and at least one surfactant selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate into the same composition:

[0257] [Formula 15]

[0258]

[0259] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0260] P1 is a C1 to C6 alkyl group;

[0261] R2 is a C1 to C6 alkyl group;

[0262] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0263] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0264] P4 is a C1 to C6 alkyl group;

[0265] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0266] P6 is a C1 to C6 alkyl group;

[0267] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0268] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0269] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0270] P9 is hydrogen or a C1 to C6 alkyl group;

[0271] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0272] P 10 It is a C1 to C6 alkyl group;

[0273] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0274] P 11(C1 to C6 alkyl).

[0275] [A78]

[0276] A method for improving the absorption of compounds represented by general formula (1),

[0277] The method comprises using a compound represented by general formula (1), its pharmaceutical salt, or a pharmaceutical solvate thereof, in combination with at least one surfactant selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate:

[0278] [Formula 16]

[0279]

[0280] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0281] P1 is a C1 to C6 alkyl group;

[0282] R2 is a C1 to C6 alkyl group;

[0283] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0284] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0285] P4 is a C1 to C6 alkyl group;

[0286] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0287] P6 is a C1 to C6 alkyl group;

[0288] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0289] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0290] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0291] P9 is hydrogen or a C1 to C6 alkyl group;

[0292] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0293] P 10 It is a C1 to C6 alkyl group;

[0294] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0295] P 11 (C1 to C6 alkyl).

[0296] [A79]

[0297] A method for improving the absorption of compounds represented by general formula (1),

[0298] The method comprises using a composition comprising a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and a composition comprising at least one surfactant selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate:

[0299] [Equation 17]

[0300]

[0301] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0302] P1 is a C1 to C6 alkyl group;

[0303] R2 is a C1 to C6 alkyl group;

[0304] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0305] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0306] P4 is a C1 to C6 alkyl group;

[0307] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0308] P6 is a C1 to C6 alkyl group;

[0309] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0310] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0311] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0312] P9 is hydrogen or a C1 to C6 alkyl group;

[0313] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0314] P 10 It is a C1 to C6 alkyl group;

[0315] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0316] P 11 (C1 to C6 alkyl).

[0317] [A80]

[0318] A method for producing a composition according to any one of [A1] to [A76], the method comprising the steps of (a) and (b):

[0319] (a) Provides a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate, and

[0320] (b) The surfactant, which is a separate component, is mixed with a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate.

[0321] [A81]

[0322] The production method according to [A80] further includes the following step (c):

[0323] (c) Mixing the solubility improver with a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate.

[0324] [A82]

[0325] A composition comprising a compound represented by formula (1a), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0326] [Formula 18]

[0327]

[0328] [A83]

[0329] A composition comprising a compound represented by formula (1a), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0330] [Formula 19]

[0331]

[0332] [A84]

[0333] A composition comprising a compound represented by formula (1a), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0334] [Formula 20]

[0335]

[0336] [A85]

[0337] A composition comprising a compound represented by formula (1b), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0338] [Equation 21]

[0339]

[0340] [A86]

[0341] A composition comprising a compound represented by formula (1b), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0342] [Equation 22]

[0343]

[0344] [A87]

[0345] A composition comprising a compound represented by formula (1b), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0346] [Equation 23]

[0347]

[0348] [A88]

[0349] A composition comprising a compound represented by formula (1c), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0350] [Equation 24]

[0351]

[0352] [A89]

[0353] A composition comprising a compound represented by formula (1c), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0354] [Equation 25]

[0355]

[0356] [A90]

[0357] A composition comprising a compound represented by formula (1c), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0358] [Equation 26]

[0359]

[0360] [A91]

[0361] A composition comprising a compound represented by formula (1d), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0362] [Equation 27]

[0363]

[0364] [A92]

[0365] A composition comprising a compound represented by formula (1d), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0366] [Equation 28]

[0367]

[0368] [A93]

[0369] A composition comprising a compound represented by formula (1d), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0370] [Equation 29]

[0371]

[0372] [A94]

[0373] A composition comprising a compound represented by formula (1e), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0374] [Formula 30]

[0375]

[0376] [A95]

[0377] A composition comprising a compound represented by formula (1e), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0378] [Equation 31]

[0379]

[0380] [A96]

[0381] A composition comprising a compound represented by formula (1e), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0382] [Equation 32]

[0383]

[0384] [A97]

[0385] A composition comprising a compound represented by formula (1f), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and lauroyl-L-carnitine.

[0386] [Equation 33]

[0387]

[0388] [A98]

[0389] A composition comprising a compound represented by formula (1f), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium lauryl sulfate.

[0390] [Formula 34]

[0391]

[0392] [A99]

[0393] A composition comprising a compound represented by formula (1f), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0394] [Formula 35]

[0395]

[0396] [A100]

[0397] The composition according to any one of [A82] to [A99] is a pharmaceutical composition for treating or preventing cancer.

[0398] [A101]

[0399] Surfactants are used to enhance the absorption of compounds represented by general formula (1).

[0400] The surfactant is at least one selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate.

[0401] [Formula 36]

[0402]

[0403] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0404] P1 is a C1 to C6 alkyl group;

[0405] R2 is a C1 to C6 alkyl group;

[0406] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0407] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0408] P4 is a C1 to C6 alkyl group;

[0409] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0410] P6 is a C1 to C6 alkyl group;

[0411] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0412] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0413] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0414] P9 is hydrogen or a C1 to C6 alkyl group;

[0415] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0416] P 10 It is a C1 to C6 alkyl group;

[0417] R 11It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0418] P 11 (C1 to C6 alkyl).

[0419] Beneficial effects of the invention

[0420] This invention provides a composition comprising a cyclic peptide compound and a surfactant, the composition having enhanced membrane permeability and / or bioavailability (BA) of the cyclic peptide compound. This invention also provides compositions comprising a cyclic peptide compound for use in combination with a surfactant. This invention further provides a method for using a surfactant to improve the membrane permeability and / or BA of a cyclic peptide compound. Detailed Implementation

[0421] Embodiments of the present invention will be described in detail below. However, the present invention is not limited to the embodiments given below.

[0422] As used herein, the term "one or more" refers to a quantity of one or two or more. When the term "one or more" is used in a context relating to substituents of a group, the term refers to a quantity from 1 to the maximum acceptable number of substituents for that group. Specific examples of the term "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or greater quantities.

[0423] As used herein, the term "to" indicates a range that includes the values ​​at both ends. For example, "A to B" means a range of A or greater and B or less.

[0424] As used herein, when used in conjunction with a numerical value, the term “about” means a range of values ​​between +10% and -10% of that value.

[0425] In this invention, the term "and / or" means any combination of "and" and "or" appropriately. Specifically, for example, the term "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, and (vii) A, B and C.

[0426] As used herein, molecular weight refers to the sum of the atomic weights of the atoms that make up a compound molecule (in units of "g / mol"), and is obtained by calculating the sum of the atomic weights of the atoms contained in the molecular formula (in units of "g / mol").

[0427] The articles “a”, “an”, and “the” used in both the specification and claims shall be interpreted as including both the singular and the plural, unless otherwise indicated herein or explicitly denied by the context.

[0428] Examples of "halogen atoms" as used in this article include F, Cl, Br, and I.

[0429] As used herein, the term "alkyl" refers to a subset of monovalent groups induced by the removal of any hydrogen atom from an aliphatic hydrocarbon and having a hydrocarbon group structure containing hydrogen and carbon atoms but no heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton. Alkyl groups include not only straight-chain forms but also branched forms. Alkyl groups particularly have 1 to 20 carbon atoms (C1 to C2). 20 The following text "C" p To C q "This refers to an alkyl group with a carbon number of p to q, preferably C1 to C2." 10 Alkyl groups, and more preferably C1 to C6 alkyl groups. Specific examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0430] As used herein, the term "alkenyl" refers to an alkenyl group having at least one double bond (two adjacent sp bonds). 2 Alkenes are monovalent groups consisting of carbon atoms. Depending on the conformation of the double bond and substituents (if present), the double bond geometry can be engegen (E) or zusammen (Z) and cis or trans conformations. Alkenes include not only straight-chain forms but also branched forms. Alkenes are preferably C2 to C3. 10 Alkenyl, more preferably C2 to C7 alkenyl or C2 to C6 alkenyl. Specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, hexenyl and 6-heptenyl.

[0431] As used herein, the term "alkynyl" is a monovalent group having at least one triple bond (two adjacent sp carbon atoms). Alynyl groups include both straight-chain and branched forms. Preferably, the alkynyl group is C2 to C3. 10 Alynyl, more preferably C2 to C6 alkynyl. Specific examples include ethynyl, 1-propynyl, propynyl, 3-butynyl, penynyl, hexynyl, 3-phenyl-2-propynyl, 3-(2'-fluorophenyl)-2-propynyl, 2-hydroxy-2-propynyl, 3-(3'-fluorophenyl)-2-propynyl and 3-methyl-(5-phenyl)-4-pentynyl.

[0432] As used herein, the term "cycloalkyl" means a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group and includes monocyclic, bicyclic, and spirocyclic groups. Cycloalkyl is preferably a C3 to C8 cycloalkyl. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclic [2.2.1]heptyl, and spiro [3.3]heptyl.

[0433] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring, and preferably C6 to C7. 10 Aryl groups. Specific examples of aryl groups include phenyl and naphthyl groups (e.g., 1-naphthyl and 2-naphthyl). As used herein, aryl groups include bicyclic aryl groups, wherein the aromatic ring is condensed with another saturated or unsaturated ring. For example, aryl groups include aryl groups having a condensed ring structure, wherein the aromatic ring is a benzene ring and the saturated ring is a 5-, 6-, or 7-membered saturated hydrocarbon ring or a saturated heterocycle. Specific examples include indenyl, 1,2,3,4-tetrahydronaphthyl, and 2,3-dihydrobenzofuran.

[0434] As used herein, the term "heterocyclic group" refers to a non-aromatic cyclic monovalent group containing a carbon atom and 1 to 5 heteroatoms. The heterocyclic group may have double and / or triple bonds in the ring. The carbon atom in the ring can be oxidized to form a carbonyl group, and the ring may be monocyclic or fused-ring. The number of atoms constituting the ring is preferably 3 to 10 (3-membered to 10-membered heterocyclic groups) or 4 to 10 (4-membered to 10-membered heterocyclic groups), more preferably 3 to 7 (3-membered to 7-membered heterocyclic groups) or 4 to 7 (4-membered to 7-membered heterocyclic groups). Specific examples of heterocyclic groups include azirrobutyl, oxetyl, oxetyl, azirrobutyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, tetrahydropyridyl, tetrahydropyrimidyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, piperazine, pyrazolyl, imidazolinyl, imidazolinyl, oxazolyl, isoxazolyl, thiazolinyl, isothiazolyl, 1,2-thiazine, thiadi Azoxyalkyl, aziridine, oxazolidinone, benzodioxyl, benzoxazolyl, dioxanepentyl, dioxyl, tetrahydropyrrolo[1,2-c]imidazol, thiohexacyclic, 3,6-diazabicyclo[3.1.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 3-oxa-8-azabicyclo[3.2.1]octyl, sulfonamide and 2-oxaspiro[3.3]heptyl.

[0435] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group containing a carbon atom and 1 to 5 heteroatoms. The ring may be a monocyclic ring, a fused ring with other rings, and may be partially saturated. The number of atoms constituting the ring is preferably 5 to 10 (5-membered to 10-membered heteroaryl), more preferably 5 to 7 (5-membered to 7-membered heteroaryl). Specific examples of heteroaryl groups include furanyl, thiopheneyl, pyrroleyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, benzothiopheneyl, benzothiadiazole, benzothiazolyl, benzooxazolyl, benzooxadiazolyl, benzoimidazolyl, indoleyl, isindoleyl, indazoleyl, quinolinyl, isoquinolinyl, cycloazolinyl, quinoxolinyl, benzodioxacyclopentenyl, indoleazinyl, and imidazopyridyl.

[0436] As used herein, the term "alkoxy" means an oxygen group bonded to an "alkyl" as defined above, and preferably a C1 to C6 alkoxy group. Specific examples of alkoxy groups include methoxy, ethoxy, 1-propoxy, 2-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and 3-methylbutoxy.

[0437] As used herein, the term "alkathio" means a thiol group bonded to an "alkyl" as defined above, and is preferably a C1 to C6 alkathio. Specific examples of alkathio include methylthio, ethylthio, 1-propanethio, 2-propanethio, n-butylthio, isobutylthio, sec-butylthio, and tert-butylthio.

[0438] As used herein, the term "olefinic group" refers to an oxy group bonded to an "olefinic" group as defined above, and is preferably a C2 to C6 olefinic group. Specific examples of olefinic groups include ethyleneoxy, allyloxy, 1-propenoxy, 2-propenoxy, 1-butenoxy, 2-butenoxy (including cis and trans), 3-butenoxy, pentenoxy, and hexenoxy.

[0439] As used herein, the term "cycloalkoxy" refers to an oxygen group bonded to a "cycloalkyl" group as defined above, and is preferably a C3 to C8 cycloalkoxy group. Specific examples of cycloalkoxy groups include cyclopropoxy, cyclobutoxy, and cyclopentoxy.

[0440] As used herein, the term "aryloxy group" refers to an oxygen group bonded to an "aryl" group as defined above, and is preferably C6 to C6. 10 Aryloxy groups. Specific examples of aryloxy groups include phenoxy, 1-naphthoxy, and 2-naphthoxy.

[0441] As used herein, the term "amino" refers in a narrow sense to -NH2 and in a broad sense to -NRR'. In this document, R and R' are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, or R and R' together with the nitrogen atom bonded thereto form a ring. Examples of amino groups preferably include -NH2, mono-C1 to C6 alkylamino groups, di-C1 to C6 alkylamino groups, and 4- to 8-membered cyclic amino groups.

[0442] As used herein, the term "monoalkylamino" means an amino group as defined above, wherein R is hydrogen and R' is an alkyl group as defined above, and preferably a mono-C1 to C6 alkylamino. Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, sec-butylamino, and tert-butylamino.

[0443] As used herein, the term "dialkylamino" means an amino group as defined above, wherein R and R' are each independently an alkyl group as defined above, and preferably a di-C1 to C6 alkylamino group. Specific examples of dialkylamino groups include dimethylamino and diethylamino.

[0444] As used herein, the term "cyclic amino" means the "amino" group as defined above, wherein R and R' form a ring together with the nitrogen atom to which they are bonded, and is preferably a 4- to 8-membered cyclic amino group. Specific examples of cyclic amino groups include 1-azacyclobutane, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 3-oxazolidinyl, 1,1-thiomorpholinyl-4-yl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-yl.

[0445] As used herein, the term "alkyl carbonyl" means a carbonyl group bonded to an "alkyl" as defined above, and preferably a C1 to C6 alkyl carbonyl. Specific examples of alkyl carbonyls include acetyl, propionyl, and butyryl. The number of carbon atoms indicated in the above definition indicates the number of carbon atoms in the alkyl moiety. For example, "C1 to C6" in "C1 to C6 alkyl carbonyl" indicates that the alkyl moiety has 1 to 6 carbon atoms.

[0446] As used herein, the term "aminocarbonyl" means a carbonyl group bonded to an "amino" group as defined above, and is preferably -CONH2, a mono-C1 to C6 alkylaminocarbonyl, a di-C1 to C6 alkylaminocarbonyl, or a 4- to 8-membered cyclic aminocarbonyl. Specific examples of aminocarbonyl groups include -CONH2, dimethylaminocarbonyl, 1-azacyclobutylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolylcarbonyl, 1,1-thiomorpholinyl-4-ylcarbonyl, and 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl.

[0447] As used herein, the term "olefin carbonyl" refers to a carbonyl group bonded to an "olefin" as defined above, and is preferably a C2 to C6 olefin carbonyl. Specific examples of olefin carbonyl include ethyleneoxycarbonyl, allyloxycarbonyl, 1-propenoxycarbonyl, 2-propenoxycarbonyl, 1-butenoxycarbonyl, 2-butenoxycarbonyl (including cis and trans), 3-butenoxycarbonyl, pentenoxycarbonyl, and hexenoxycarbonyl.

[0448] As used herein, the term "alkylsulfonyl" means a sulfonyl group bonded to an "alkyl" as defined above, and is preferably a C1 to C6 alkylsulfonyl group. Specific examples of alkylsulfonyl groups include methanesulfonyl groups.

[0449] As used herein, the term "haloalkyl" means a group in which one or more hydrogen atoms of the "alkyl" as defined above are replaced by a halogen, and is preferably a C1 to C6 haloalkyl, more preferably a C1 to C6 fluoroalkyl. Specific examples of haloalkyl include difluoromethyl, trifluoromethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3-difluoropropyl, 4,4-difluorobutyl, 5,5-difluoropentyl, and 1,1-difluoroethyl.

[0450] As used herein, the term "aminoalkyl" means a group in which one or more hydrogens of the "alkyl" as defined above are replaced by the "amino" as defined above, and is preferably a C1 to C6 aminoalkyl. Specific examples of aminoalkyl include 1-pyridylmethyl, 2-(1-piperidinyl)ethyl, 3-(1-piperidinyl)propyl, 4-aminobutyl, and 2-aminoethyl.

[0451] As used herein, the term "cycloalkylalkyl" means a group in which one or more hydrogen atoms of the "alkyl" as defined above are replaced by the "cycloalkyl" as defined above, and is preferably a C3 to C8 cycloalkyl C1 to C6 alkyl, more preferably a C3 to C6 cycloalkyl C1 to C2 alkyl. Specific examples of cycloalkylalkyl include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0452] As used herein, the term "aralkyl (arylalkyl)" means a group in which at least one hydrogen atom of the "alkyl" as defined above is replaced by an "aryl" as defined above, and preferably is C7 to C8. 14 Aryl alkyl group, more preferably C7 to C8 10 Araneyl groups. Specific examples of araneyl groups include benzyl, phenethyl, and 3-phenylpropyl.

[0453] As used herein, the term "alkylene" means a divalent group induced by further removing any hydrogen atom from the aforementioned "alkyl", and is preferably a C4 to C8 alkylene. Specific examples of alkylene include -CH2-, -(CH2)2-, -(CH2)3-, -CH(CH3)CH2-, -C(CH3)2-, -(CH2)4-, -CH(CH3)CH2CH2-, -C(CH3)2CH2-, -CH2CH(CH3)CH2-, -CH2C(CH3)2-, -CH2CH2CH(CH3)-, -(CH2)5-, -(CH2)6-, -(CH2)7-, and -(CH2)8-.

[0454] As used herein, the term "alkenyl" refers to a divalent group induced by further removal of any hydrogen atom from the aforementioned "alkenyl". Depending on the conformation of the double bond and substituents (if present), the geometry of the double bond can be engegen (E) or zusammen (Z) and cis or trans conformations. Alkenyl groups include straight-chain or branched forms, and are preferably C2 to C3. 10 Alkenyl, more preferably C2 to C6 alkenyl.

[0455] As used herein, the term "ynynyl" refers to a divalent group induced by further removing any hydrogen atom from the aforementioned "ynyl". Iynyl groups include straight-chain or branched forms, and are preferably C2 to C3. 10 Imyynyl, more preferably C2 to C6 ynylyl.

[0456] As used herein, the term "alicyclic ring" refers to a non-aromatic hydrocarbon ring. Alicyclic rings may have unsaturated bonds in the ring and may be polycyclic with two or more rings. The carbon atoms constituting the ring may be oxidized to form carbonyl groups. Alicyclic rings are preferably 3- to 8-membered alicyclic rings. Specific examples include cyclopropane rings, cyclobutane rings, cyclopentane rings, cyclohexane rings, cycloheptane rings, cyclooctane rings, and bicyclic [2.2.1]heptane rings.

[0457] As used herein, the term "saturated heterocycle" refers to a non-aromatic heterocycle containing a carbon atom and 1 to 5 heteroatoms and without double and / or triple bonds. A saturated heterocycle can be a monocyclic ring or can form a fused ring with another ring (e.g., an aromatic ring such as a benzene ring). Saturated heterocycles are preferably 4- to 7-membered saturated heterocycles. Specific examples include nitrogen-containing butane rings, oxo-containing butane rings, tetrahydrofuran rings, tetrahydropyran rings, morpholine rings, thiomorpholine rings, pyrrolidine rings, 4-oxopyrrolidine rings, piperidine rings, 4-oxopiperidine rings, piperazine rings, pyrazolidine rings, imidazoline rings, oxazolidine rings, isoxazolidine rings, thiazoline rings, isothiazolidine rings, thiadiazoline rings, oxazolidine ketone rings, dioxolane rings, dioxane rings, thio-containing butane rings, octahydroindole rings, dihydroindole rings, and nitrogen-containing heptane rings.

[0458] As used herein, the term “optionally substituted” means that a group may be substituted by any substituent.

[0459] Examples of substituents containing halogen atoms in this article include halogen-derived substituents having halogen as a substituent, alkyl groups, cycloalkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, and aralkyl groups, and more specifically fluoroalkyl, difluoroalkyl, and trifluoroalkyl groups.

[0460] Examples of halogen-derived substituents include fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0461] Examples of substituents containing an O atom include groups such as hydroxyl (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxyl (-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), aminosulfonylamino (-NH-SO2-NHR), thiocarboxyl (-C(=O)-SH), and carboxylcarbonyl (-C(=O)-CO2H).

[0462] Examples of alkoxy groups (-OR) include alkoxy, cycloalkoxy, alkenoxy, alkynoxy, aryloxy, heteroaryloxy, and arylalkoxy. The alkoxy group is preferably a C1 to C4 alkoxy or a C1 or C2 alkoxy, and particularly preferably a methoxy or ethoxy group.

[0463] Examples of carbonyl groups (-C(=O)-R) include formyl (-C(=O)-H), alkyl carbonyl, cycloalkyl carbonyl, alkenyl carbonyl, alkynyl carbonyl, aryl carbonyl, heteroaryl carbonyl, and aralkyl carbonyl.

[0464] Examples of oxycarbonyl groups (-C(=O)-OR) include alkoxycarbonyl, cycloalkoxycarbonyl, alkenoxycarbonyl, alkynoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, and arylalkoxycarbonyl.

[0465] Examples of carbonyl groups (-OC(=O)-R) include alkyl carbonyl groups, cycloalkyl carbonyl groups, alkenyl carbonyl groups, alkynyl carbonyl groups, aryl carbonyl groups, heteroaryl carbonyl groups, and aralkyl carbonyl groups.

[0466] Examples of thiocarbonyl (-C(=O)-SR) include alkyl thiocarbonyl, cycloalkyl thiocarbonyl, alkenyl thiocarbonyl, alkynyl thiocarbonyl, aryl thiocarbonyl, heteroaryl thiocarbonyl, and aralkyl thiocarbonyl.

[0467] Examples of carbonyl thio groups (-SC(=O)-R) include alkyl carbonyl thio, cycloalkyl carbonyl thio, alkenyl carbonyl thio, alkynyl carbonyl thio, aryl carbonyl thio, heteroaryl carbonyl thio, and aralkyl carbonyl thio.

[0468] Examples of aminocarbonyl groups (-C(=O)-NHR) include alkylaminocarbonyl groups (e.g., C1 to C6 or C1 to C4 alkylaminocarbonyl groups, particularly ethylaminocarbonyl and methylaminocarbonyl), cycloalkylaminocarbonyl groups, alkenylaminocarbonyl groups, alkynylaminocarbonyl groups, arylaminocarbonyl groups, heteroarylaminocarbonyl groups, and aralkylaminocarbonyl groups. Further examples include groups in which the H atom bonded to the N atom in -C(=O)-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0469] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, and aralkylcarbonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0470] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenoxycarbonylamino, alkynoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, and arylalkoxycarbonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or arylalkyl group.

[0471] Examples of sulfonylamino (-NH-SO2-R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, and aralkylsulfonylamino. Further examples include compounds in which the H atom bonded to the N atom in -NH-SO2-R is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0472] Examples of aminosulfonyl (-SO2-NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, and aralkylaminosulfonyl. Further examples include compounds in which the H atom bonded to the N atom in -SO2-NHR is further replaced by an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl group.

[0473] Examples of aminosulfonylamino (-NH-SO2-NHR) include alkylaminosulfonylamino, cycloalkylaminosulfonylamino, alkenylaminosulfonylamino, alkynylaminosulfonylamino, arylaminosulfonylamino, heteroarylaminosulfonylamino, and aralkylaminosulfonylamino. The two hydrogen atoms bonded to the nitrogen atom in -NH-SO2-NHR can be substituted by substituents, each independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, and these two substituents can form a ring.

[0474] Examples of substituents containing an S atom include groups such as thiol (-SH), thio (-SR), sulfinyl (-S(=O)-R), sulfonyl (-SO2-R), and sulfonyl (-SO3H).

[0475] Examples of selectable thio groups (-SR) include alkylthio, cycloalkylthio, olefin thio, alkynylthio, aryl thio, heteroaryl thio, and arylalkyl thio.

[0476] Examples of sulfinyl groups (-S(=O)-R) include alkyl sulfinyl groups, cycloalkyl sulfinyl groups, alkenyl sulfinyl groups, alkynyl sulfinyl groups, aryl sulfinyl groups, heteroaryl sulfinyl groups, and aralkyl sulfinyl groups.

[0477] Examples of sulfonyl groups (-SO2-R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, and aralkylsulfonyl.

[0478] Examples of substituents containing an N atom include groups such as azide (-N3; also known as "azide group"), cyano (-CN), primary amino (-NH2), secondary amino (-NH-R; also known as monosubstituted amino), tertiary amino (-NR(R'); also known as disubstituted amino), amido (-C(=NH)-NH2), substituted amido (-C(=NR)-NR'R"), guanidino (-NH-C(=NH)-NH2), substituted guanidino (-NR-C(=NR''')-NR'R"), and aminocarbonylamino (-NR-CO-NR'R").

[0479] Examples of secondary amino groups (-NH-R: monosubstituted amino) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0480] Examples of tertiary amino groups (-NR(R'): disubstituted amino groups) include amino groups having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl (aralkyl)amino groups. These two substituents can form a ring. Specific examples include dialkylamino groups, particularly C1-C6 dialkylamino groups, C1-C4 dialkylamino groups, dimethylamino groups, and diethylamino groups. As used herein, the term "C" refers to... p -C q "Dialkylamino group" refers to a group in which the amino group is bonded by two carbon atoms. p -C q An alkyl-substituted group. Two carbon atoms. p -C q The alkyl groups may be the same or different.

[0481] Examples of substituted amidoyl groups (-C(=NR)-NR'R") include those in which the three substituents R, R', and R" on the N atom are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, such as alkyl(aralkyl)(aryl)amidinyl.

[0482] Examples of substituted guanidino groups (-NR-C(=NR''')-NR'R") include those in which R, R', R" and R''' are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and aralkyl groups, or those that form a ring.

[0483] Examples of aminocarbonylamino (-NR-CO-NR'R") include those in which R, R', and R" are each independently selected from hydrogen atoms, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl groups, or those groups that form a ring.

[0484] Examples of substituents containing a B atom include boryl (-BR(R')) and dioxoboryl (-B(OR)(OR')). The two substituents R and R' can be groups independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or can be groups that form a ring. Specific examples include cyclic boryl groups, and more specifically, pinacol boryl groups, neopentyl glycol boryl groups, and catechol boryl groups.

[0485] [Composition]

[0486] The composition according to this embodiment comprises the following components (1) and / or (2).

[0487] (1) A compound represented by general formula (1), its medicinal salt, or its medicinal solvate.

[0488] [Formula 37]

[0489]

[0490] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl C1 to C6 alkyl;]

[0491] P1 is a C1 to C6 alkyl group;

[0492] R2 is a C1 to C6 alkyl group;

[0493] R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle;

[0494] Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0495] P4 is a C1 to C6 alkyl group;

[0496] R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl;

[0497] P6 is a C1 to C6 alkyl group;

[0498] R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy;

[0499] R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group.

[0500] R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups;

[0501] P9 is hydrogen or a C1 to C6 alkyl group;

[0502] R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl;

[0503] P 10 It is a C1 to C6 alkyl group;

[0504] R 11 It is a di-C1 to C6 alkylaminocarbonyl or a 4- to 8-membered cyclic aminocarbonyl; and

[0505] P 11 (C1 to C6 alkyl).

[0506] (2) Surfactants.

[0507] [(1) Compounds represented by general formula (1), their medicinal salts, or their medicinal solvates]

[0508] As used herein, compounds represented by general formula (1) are also simply referred to as “compounds” or “cyclic peptide compounds”.

[0509] Examples of pharmaceutical salts of the compounds according to this embodiment include: hydrochlorides; hydrobromides; hydroiodates; phosphates; phosphonates; sulfates; sulfonates, such as methanesulfonates and p-toluenesulfonates; carboxylates, such as acetates, citrates, malates, tartrates, succinates, and salicylates; or alkali metal salts, such as sodium and potassium salts; alkaline earth metal salts, such as magnesium and calcium salts; and ammonium salts, such as ammonium salts, alkylammonium salts, dialkylammonium salts, trialkylammonium salts, and tetraalkylammonium salts. These salts are produced, for example, by contacting the compound with an acid or base that can be used to produce a pharmaceutical product. A solvate of the compound or its pharmaceutical salt according to this embodiment is a solvate in which the compound or its pharmaceutical salt forms a molecular aggregate together with a solvent, and is referred to as a hydrate when the solvent is water. A solvate of the compound or its pharmaceutical salt according to this embodiment is preferably a hydrate, and specific examples of hydrates include monohydrates to decahydrates, preferably monohydrates to pentahydrates, and more preferably monohydrates to trihydrates. The solvates of the compounds or their pharmaceutical salts according to this embodiment include not only solvates having a single solvent (such as water, alcohol (e.g., methanol, ethanol, 1-propanol or 2-propanol) or dimethylformamide), but also solvates having multiple solvents.

[0510] In one respect, in general formula (1), R1 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl C1 to C6 alkyl. Specific examples of R1 in this regard include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl.

[0511] R1 is preferably a C1 to C4 alkyl or a C4 to C6 cycloalkyl C1 to C3 alkyl, more preferably a C2 to C4 alkyl or a C5 to C6 cycloalkyl C1 to C2 alkyl, and even more preferably ethyl, n-propyl, 2-methylpropyl or cyclopentylmethyl.

[0512] In one respect, in general formula (1), P1 is a C1 to C6 alkyl group. Specific examples of P1 in this respect include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0513] P1 is preferably a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and even more preferably a methyl group.

[0514] In one respect, in general formula (1), R2 is a C1 to C6 alkyl group. Specific examples of R2 in this respect include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0515] R2 is preferably a C3 to C6 alkyl, more preferably a C4 to C5 alkyl, and even more preferably sec-butyl (1-methylpropyl).

[0516] In one aspect, in general formula (1), R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably a 4- to 6-membered saturated heterocycle, and more preferably a 5-membered saturated heterocycle. Specific examples of 4- to 7-membered saturated heterocycles include nitrogen-containing butane rings, pyrrolidine rings, piperidine rings, piperazine rings, and morpholine rings, with pyrrolidine rings being preferred.

[0517] On one hand, in general formula (1), P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl, except when R3 and P3 form a 4- to 7-membered saturated heterocycle. When R3 and P3 form a 4- to 7-membered saturated heterocycle, the 4- to 7-membered saturated heterocycle is as described above. When P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl... When cycloalkyl, specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl.

[0518] When P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl, P3 is preferably a C1 to C3 alkyl or a C3 to C6 cycloalkyl, more preferably a C1 to C2 alkyl or a C3 to C4 cycloalkyl, and even more preferably methyl or cyclopropyl.

[0519] In one respect, in general formula (1), P4 is a C1 to C6 alkyl group. Specific examples of P4 in this respect include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0520] P4 is preferably a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and even more preferably a methyl group.

[0521] In one aspect, in general formula (1), R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl, and C3 to C8 cycloalkyl. When one or more substituents are present, the substituents are preferably one or more groups selected from the group consisting of C1 to C3 alkyl, C1 to C3 haloalkyl, and C3 to C6 cycloalkyl, more preferably one or more groups selected from the group consisting of C1 to C3 alkyl and C1 to C3 fluoroalkyl, and even more preferably groups selected from the group consisting of methyl and trifluoromethyl.

[0522] R5 is preferably a benzyl group optionally substituted with one or more groups selected from the group consisting of C1 to C3 cycloalkyl, C1 to C3 haloalkyl and C3 to C6 cycloalkyl, more preferably a benzyl group optionally substituted with one or more groups selected from the group consisting of C1 to C3 alkyl and C1 to C3 fluoroalkyl, further preferably a benzyl group optionally substituted with one or more groups selected from the group consisting of methyl and trifluoromethyl, and particularly preferably 4-methylbenzyl and 4-trifluoromethylbenzyl.

[0523] In one respect, in general formula (1), P6 is a C1 to C6 alkyl group. Specific examples of P6 in this respect include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0524] P6 is preferably a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and even more preferably a methyl group.

[0525] In one aspect, in general formula (1), R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl, and C1 to C6 alkoxy. When one or more substituents are present, the substituents are preferably one or more groups selected from the group consisting of halogen, C1 to C3 haloalkyl, and C1 to C3 alkoxy, more preferably one or more groups selected from the group consisting of F, C1 to C3 fluoroalkyl, and C1 to C3 alkoxy, and even more preferably groups selected from the group consisting of F, trifluoromethyl, and methoxy.

[0526] R7 is preferably a phenethyl group optionally substituted with one or more groups selected from the group consisting of halogen, C1 to C3 haloalkyl and C1 to C3 alkoxy, more preferably a phenethyl group optionally substituted with one or more groups selected from the group consisting of F, C1 to C3 fluoroalkyl and C1 to C3 alkoxy, further preferably a phenethyl group optionally substituted with one or more groups selected from the group consisting of F, trifluoromethyl and methoxy, and particularly preferably 3,5-difluoro-4-trifluoromethylphenethyl and 3-methoxy-4-trifluoromethylphenethyl.

[0527] In one aspect, in general formula (1), R8, together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8, forms a 4- to 7-membered saturated heterocycle. In this case, the 4- to 7-membered saturated heterocycle is preferably a 4- to 6-membered saturated heterocycle, and more preferably a 5-membered saturated heterocycle. Specific examples of 4- to 7-membered saturated heterocycles include nitrogen-containing butane rings, pyrrolidine rings, piperidine rings, piperazine rings, and morpholine rings, with pyrrolidine rings being preferred. The 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group. When substituted, the substituent is preferably a C1 to C3 alkoxy group, more preferably a C1 to C2 alkoxy group, and even more preferably an ethoxy group.

[0528] In one aspect, in general formula (1), R9, together with Q9 and the carbon atoms bonded to R9 and Q9, forms a 3- to 8-membered alicyclic ring. In this case, the 3- to 8-membered alicyclic ring is preferably a 4- to 6-membered alicyclic ring, and more preferably a 4- to 5-membered alicyclic ring. Specific examples of the 3- to 8-membered alicyclic ring include cyclopropane, cyclobutane, cyclopentane, and cyclohexane rings, with cyclobutane and cyclopentane rings being preferred. The 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups. When substituted, the substituent is preferably a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and further preferably methyl.

[0529] In one respect, in general formula (1), P9 is hydrogen or a C1 to C6 alkyl group. Specific examples of P9 in this respect include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0530] P9 is preferably hydrogen or C1 to C3 alkyl, more preferably hydrogen or C1 to C2 alkyl, and even more preferably hydrogen or methyl.

[0531] On the one hand, in general formula (1), R 10It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl. In this respect, R 10 Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl and spiro[3.3]heptyl.

[0532] R 10 Preferably, it is a C3 to C6 alkyl or a C4 to C6 cycloalkyl, more preferably a C4 to C6 cycloalkyl, and even more preferably cyclopentyl.

[0533] On the one hand, in general formula (1), P 10 It is a C1 to C6 alkyl group. In this respect, P 10 Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0534] P 10 Preferably, it is a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and even more preferably methyl.

[0535] On the one hand, in general formula (1), R 11 It is a di-C1 to C6 alkylamino carbonyl or a 4- to 8-membered cyclic amino carbonyl. In this respect, R 11Specific examples include dimethylaminocarbonyl, 1-azacyclobutanecarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolylcarbonyl, 1,1-dioxoanionylthiomorpholinyl-4-ylcarbonyl and 3-oxa-8-azabicyclo[3.2.1]octane-8-ylcarbonyl.

[0536] R 11 Preferably, it is a di-C1 to C3 alkylaminocarbonyl or a 4- to 6-membered cyclic aminocarbonyl, more preferably a di-C1 to C3 alkylaminocarbonyl, and even more preferably a dimethylaminocarbonyl.

[0537] On the one hand, in general formula (1), P 11 It is a C1 to C6 alkyl group. In this respect, P 11 Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl (2-methylpropyl), n-pentyl, sec-pentyl (1-methylbutyl), tert-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, and 3,3-dimethylbutyl.

[0538] P 11 Preferably, it is a C1 to C3 alkyl group, more preferably a C1 to C2 alkyl group, and even more preferably methyl.

[0539] Specific examples of compounds according to this embodiment include those represented by formulas (1a), (1b), (1c), (1d), (1e), and (1f). The compounds represented by formulas (1a), (1b), (1c), (1d), (1e), and (1f) correspond to compounds CP05, CP01, CP02, CP03, CP04, and CP06 in the examples, respectively.

[0540] [Formula 38]

[0541]

[0542] [Formula 39]

[0543]

[0544] [Formula 40]

[0545]

[0546] [Formula 41]

[0547]

[0548] [Equation 42]

[0549]

[0550] [Formula 43]

[0551]

[0552] The cyclic peptide compound according to this embodiment can be synthesized, for example, according to the method described in Patent Document 3.

[0553] The Caco-2 Papp (cm / sec) value of the cyclic peptide compound according to this embodiment, measured in a system without the surfactant according to this embodiment, is 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, 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 smaller, 8.4E-7 or smaller, 8.2E-7 or smaller, 8.0E-7 or smaller, 7.8E-7 or smaller, 7.6E-7 or smaller, 7.4E-7 or smaller, 7.2E-7 or smaller, 7.0E-7 or smaller, 6.8E-7 or smaller, 6.6E-7 or smaller, 6.4E-7 or smaller, 6.2E-7 or smaller, 6.0E-7 or smaller, 5.8E-7 or smaller, 5.6E-7 or smaller, 5.4E-7 or smaller, 5.2E-7 or smaller, 5.0E-7 or smaller, 4.8E-7 or smaller, 4.6E-7 or smaller, 4.4E-7 or smaller, 4.2E-7 or smaller, 4.0E-7 or smaller, 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, or 1.0E-7 or less. Note that En (where n is a natural number) refers to 10. -n (For example, 1.0E-5 = 1.0 × 10) -5 ).

[0554] The Caco-2 Papp (cm / sec) value of the cyclic peptide compound according to this embodiment, as measured in a system containing the surfactant according to this embodiment, is preferably 1.0E-9 or greater, 1.0E-8 or greater, 2.0E-8 or greater, 3.0E-8 or greater, 4.0E-8 or greater, 5.0E-8 or greater, 6.0E-8 or greater, 7.0E-8 or greater, 8.0E-8 or greater, 9.0E-8 or greater, 1.0E-7 or greater, 1.1E-7 or greater, 1.2E-7 or greater, 1.3E-7 or greater, 1.4E-7 or greater, 1.5E-7 or greater, 1.6E-7 or greater, 1.7E-7 or greater, 1.8E-7 or greater, 1.9E-7 or greater, or 2.0E-7 or greater.

[0555] The value of Caco-2 Papp (cm / sec) of the cyclic peptide compound according to this embodiment, as measured in a system containing the surfactant according to this embodiment, is preferably 1.1 times or more, more preferably 1.2 times or more, even more preferably 1.5 times or more, even more preferably 2 times or more, even more preferably 3 times or more, even more preferably 5 times or more, than the value measured in a system without the surfactant.

[0556] The value of Caco-2 Papp (cm / sec) serves as an indicator of membrane permeability in the cell membrane and can be measured by the following methods.

[0557] (i) Caco-2 cells were cultured on plates (e.g., 96-well Transwell and Falcon(R)96) for 3 weeks, and then the composition to be evaluated and FaSSIF / HBSS buffer (pH 6.5) were added to the top side, and HBSS buffer containing 4% BSA (pH 7.4) was added to the bottom side (start of permeability studies).

[0558] (ii) Each well was shaken at 80 rpm at 37°C and 5% CO2, and 180 minutes after the start, the sample on the substrate side was taken and the permeation of the cyclic peptide compound was measured by liquid chromatography-mass spectrometry (LC / MS / MS).

[0559] (iii) Calculate the permeability coefficient (Caco-2 Papp (cm / sec)) from the measured permeability.

[0560] In the above measurements, Pgp inhibitors (such as Zosuquidar) can be added to the FaSSIF / HBSS buffer and HBSS buffer, respectively.

[0561] After step (i) and before step (ii) above, pre-incubation can be performed by placing each well at 5% CO2, 37°C and 80 rpm for 20 to 24 hours.

[0562] After pre-incubation, the substrate-side solution can be removed and washed, and a fresh solution of the same composition can be added. A Pgp inhibitor can also be added to the 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).

[0563] Additionally, the concentration of the substance to be evaluated on the donor side used to calculate the permeability coefficient in step (iii) above can be the initial concentration added, or the concentration measured by collecting the solution on the tip side before starting pre-incubation or shaking in step (ii) above. In particular, when performing pre-incubation, it is preferable to use the concentration of the solution collected on the tip side before pre-incubation.

[0564] Specifically, the concentration can be measured using the method described in the example.

[0565] In this way, when measuring the Caco-2 Papp (cm / sec) of the composition according to this embodiment, the substance to be measured is the cyclic peptide compound contained in the composition.

[0566] The bioavailability (BA) value of the cyclic peptide compound according to this embodiment, as measured in a system containing the surfactant according to this embodiment, is preferably 1.1 times or greater than the value measured in a system without the surfactant, more preferably 1.2 times or greater, even more preferably 1.4 times or greater, even more preferably 1.6 times or greater, even more preferably 1.8 times or greater, even more preferably 2.0 times or greater.

[0567] Bioavailability (BA) values ​​can be measured, for example, by administering the composition to be evaluated to test animals and collecting blood over time from the jugular vein using a syringe for up to 24 hours after administration. The blood is dispensed into tubes treated with heparin as an anticoagulant and centrifuged to separate the plasma. After deproteinization with acetonitrile, the plasma concentration of the cyclic peptide compound is measured using an LC / MS / MS apparatus (e.g., an XEVO TQ-XS manufactured by Waters Corporation). Based on the resulting changes in plasma concentration, pharmacokinetic parameters are calculated using non-compartmental analysis with the analytical software Phoenix WinNonlin 8.2 (manufactured by Certara LP).

[0568] [(2) Surfactants]

[0569] The surfactant according to this embodiment is preferably at least one or more of the group consisting of: (A) a surfactant having a linear alkylene structure, a linear alkenyl structure, or a linear alkyne structure and having 5 or more and 13 or fewer carbon atoms in the structure, and (B) a surfactant having carnitine residues. The surfactant may be used alone or in combination of two or more. Specific examples of surfactants described below may be used in the form of salts (e.g., hydrochloride salts and sodium salts).

[0570] According to one embodiment, the surfactant may be a component that promotes the emulsification and dispersion of cyclic peptide compounds, a component that promotes absorption via transcellular pathways, or a component that promotes absorption via paracellular pathways.

[0571] The surfactant according to one embodiment has a linear alkylene structure, a linear alkenylene structure, or a linear alkyneylene structure, and the number of carbon atoms contained in the structure is 5 or more and 13 or less. The number of carbon atoms is preferably 6 or more, more preferably 8 or more, further preferably 10 or more, and particularly preferably 11. The number of carbon atoms contained in the linear alkylene structure may be 6 or more and 13 or less, preferably 8 or more and 12 or less, more preferably 10 or more and 12 or less, and particularly preferably 11.

[0572] Specific examples of surfactants are shown below (the numbers in parentheses represent the number of carbon atoms in the linear alkylene structure).

[0573] (a) Hexanoic acid (5)

[0574] (b) Bitterness (7)

[0575] (c) Decanoic acid (9)

[0576] (d) Lauric acid (11)

[0577] (e) Lauroylcarnitine (11)

[0578] (f) Lauroyl-L-carnitine (11)

[0579] (g) Carnitine palmitate (15)

[0580] According to one embodiment, the surfactant is preferably a compound represented by any of the following general formulas (a1) to (a3):

[0581] [Formula 44]

[0582]

[0583] [Formula 45]

[0584]

[0585] [Formula 46]

[0586]

[0587] In general formulas (a1) to (a3), R S1 X represents a saturated or unsaturated straight-chain hydrocarbon group having 5 or more and 13 or fewer carbon atoms that may have substituents, where X represents sodium or potassium, and Y represents a group or stereoisomer of the group represented by the following formula (a4).

[0588] "Hydrocarbon group" refers to "alkyl", "alkenyl", and "alkynyl". Saturated hydrocarbon groups are alkyl, and unsaturated hydrocarbon groups are alkenyl or alkynyl.

[0589] [Formula 47]

[0590]

[0591] In general formulas (a1) to (a3), R S1 Preferably, it is an alkyl group having 5 or more and 13 or fewer carbon atoms, more preferably an alkyl group having 7 or more and 12 or fewer carbon atoms, further preferably an alkyl group having 8 or more and 12 or fewer carbon atoms, further more preferably an alkyl group having 10 or more and 12 or fewer carbon atoms, and particularly preferably an alkyl group having 11 carbon atoms. S1 It is also preferably a straight-chain alkyl group. And R S1Preferably, it is an unsubstituted alkyl group. In formula (a4),

[0592] [Formula 48]

[0593]

[0594] Indicates a key.

[0595] The surfactant according to one embodiment also contains a medium-chain fatty acid structure. A medium-chain fatty acid is a fatty acid having 6 or more and 12 or fewer carbon atoms. More preferably, the number of carbon atoms in the medium-chain fatty acid structure is 8 or more, further preferably 10 or more, and particularly preferably 12.

[0596] According to one embodiment, the surfactant may be a medium-chain fatty acid ester, a sodium salt of a medium-chain fatty acid, or a potassium salt of a 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 the medium-chain fatty acid and the hydroxyl group of a compound containing a hydroxyl group. Examples of medium-chain fatty acids include, but are not limited to, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid, and lauric acid, more preferably dioctanoic acid, decanoic acid, and lauric acid, and even more preferably lauric acid. Examples of compounds containing hydroxyl groups include, but are not limited to, aliphatic alcohols, polyols, and betaines containing hydroxyl groups, such as carnitine, trimethylglycine, and proline betaine.

[0597] According to one embodiment, the surfactant is preferably acylcarnitine, more preferably lauroylcarnitine or carnitine palmitate, more preferably lauroylcarnitine, and particularly preferably lauroyl-L-carnitine.

[0598] According to one embodiment, the surfactant has carnitine residues. The surfactant having carnitine residues is preferably an acylcarnitine. An acylcarnitine is a compound in which an ester bond is formed between the hydroxyl group of the carnitine and the carboxyl group of a compound containing a carboxyl group. The carnitine may be in D- or L-form. The compound containing the carboxyl group may be an organic acid, preferably a medium-chain fatty acid, such as a saturated or unsaturated fatty acid, more preferably a saturated fatty acid. The medium-chain fatty acid preferably has 6 or more carbon atoms, more preferably 8 or more, further preferably 10 or more, and particularly preferably 12. The saturated fatty acid preferably has 6 or more carbon atoms, more preferably 8 or more, further preferably 10 or more, and particularly preferably 12. Examples of saturated fatty acids according to the invention include hexanoic acid, caprylic acid, capric acid, and lauric acid. The acylcarnitine according to the invention is more preferably lauroylcarnitine or carnitine palmitate, more preferably lauroylcarnitine, and particularly preferably lauroyl-L-carnitine.

[0599] According to one embodiment, the surfactant may be an alkyl carboxylate or an alkyl sulfate. The alkyl carboxylate is preferably an octanoate, and more preferably sodium deoctanoate. The alkyl sulfate is preferably a lauryl sulfate, and more preferably sodium lauryl sulfate.

[0600] Examples of surfactants according to this embodiment preferably include surfactants selected from the group consisting of: lauroyl-L-carnitine, sodium octanoate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0601] A surfactant according to one embodiment is added as a separate component to the composition according to this embodiment.

[0602] [Solubility improver]

[0603] The compositions according to this embodiment may further include solubility improvers that enhance the solubility of the cyclic peptide compound. Examples of components that enhance the solubility of the cyclic peptide compound include various oily components, polymers that form solid dispersions (amorphous solid dispersions, hereinafter also referred to as "ASD") with the cyclic peptide compound, and pH-adjusting components. Solubility improvers may be used alone or in combination of two or more.

[0604] Preferred specific examples of oily components may include fatty acids such as oleic acid, stearic acid, linoleic acid, palmitic acid, linolenic acid, and myristic acid; olive oil, almond oil, coconut oil, cocoa butter, macadamia nut oil, avocado oil, safflower oil, soybean oil, flaxseed oil, rapeseed oil, castor oil, palm oil, high-oil sunflower oil, high-oil safflower oil, sunflower oil, cottonseed oil, corn oil, sesame oil, peanut oil, almond oil, tung oil, grapeseed oil, pistachio seed oil, sunflower oil, hazelnut oil, jojoba oil, meadowfoam seed oil, rosehip oil, trihexyhexylglycerol, tricaprylylglycerol, tricaprylylglycerol, tripalmitoylglycerol, trioleoylglycerol, trilinoleic acid, trilinolenic acid, trilinolenic acid, triarachidonic acid, and trisorcinol. In addition to the components listed above, examples of oily components include vegetable oils collected from plants, vegetable oils partially decomposed through their hydrolysis, and vegetable oils that have been separated and purified. Oily components can also be obtained by synthetic methods.

[0605] Regarding the oily component, it is further preferred to use a compound with a polyoxyethylene structure added to the oily component as a solubility improver. The polyoxyethylene structure consists of -(CH2-CH2-O). n- indicates. In this compound, the average molar number of added ethylene oxide is preferably 2 or more and 100 or less, more preferably 3 or more and 80 or less, further preferably 3 or more and 60 or less, and even more preferably 3 or more and 50 or less. The average molar number of added ethylene oxide is also preferably 5 or more and 40 or less, more preferably 10 or more and 40 or less, further preferably 20 or more and 40 or less, and even more preferably 30 or more and 40 or less.

[0606] Specific examples of the added compounds having a polyoxyethylene structure include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid esters. Polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, and polyoxyethylene sorbitan fatty acid esters are preferred, polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid esters are more preferred, polyoxyethylene castor oil having an average molar number of ethylene oxide of 30 or greater and 40 or less, and polyoxyethylene sorbitan fatty acid ester having an average molar number of ethylene oxide of 10 or greater and 40 or less are even more preferred, and polyoxyethylene castor oil 35 (e.g., Cremophor EL) and polyoxyethylene (20) sorbitan monooleate (Tween 80) are even more preferred.

[0607] Examples of polymers that form ASD with cyclic peptide compounds include polyethylene glycol, polyvinylpyrrolidone, copovidone, polyvinyl alcohol, cellulose-based polymers, and methacrylic acid-methacrylic acid copolymers. Specific examples include vinyl polymers and copolymers having at least one substituent selected from hydroxyl, alkyl acyloxy, and cyclic amide groups; vinyl copolymers having at least one hydrophilic repeating unit containing a hydroxyl group and at least one hydrophobic repeating unit containing an alkyl or aryl group; polyvinyl alcohol; polyvinyl alcohol having at least a portion of repeating units in the form of non-hydrolyzed (vinyl acetate); polyvinyl alcohol-polyvinyl acetate copolymers; polyvinylpyrrolidone; copovidone; copolymers of acrylates and methacrylic acid; polyvinyl alcohol-polyoxyethylene copolymers; polyoxyethylene-polyoxypropylene block copolymers (also known as poloxamers); polyethylene glycol; hydroxypropyl methylcellulose acetate (HPMCA); hydroxypropyl... Hydroxypropyl cellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose, 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, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, polyvinyl alcohol 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.

[0608] 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.

[0609] [Composition]

[0610] Regarding the content of (1) the compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate (hereinafter also referred to as "component (1)") and (2) the surfactant (hereinafter also referred to as "component (2)") in the composition according to this embodiment, based on 1 part by mass of component (1), component (2) 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. In addition, based on 1 part by mass of component (1), component (2) 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. Furthermore, based on 1 part by mass of component (1), the content of component (2) can 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. When component (1) contains two or more cyclic peptide compounds, the above ranges are its total amount. The same applies to component (2). The contents of components (1) and (2) in the composition can be measured by liquid chromatography-mass spectrometry (LC-MS), liquid chromatography with charged electrosol detection, or nuclear magnetic resonance (NMR).

[0611] Furthermore, when component (2) is liquid at 25°C, the content of component (2) is preferably 0.05 vol% or more, more preferably 0.075 vol% or more, further preferably 0.1 vol% or more, further preferably 0.2 vol% or more, further preferably 0.3 vol% or more, further preferably 0.5 vol% or more, further preferably 0.8 vol% or more, and further preferably 1.0 vol% or more. The content of component (2) is also preferably 100 vol% or less, more preferably 85 vol% or less, further preferably 50 vol% or less, further preferably 40 vol% or less, further preferably 30 vol% or less, further preferably 20 vol% or less, further preferably 15 vol% or less, and further preferably 10 vol% or less. The content of component (2) is preferably 0.05 vol% or more and 50 vol% or less, more preferably 0.3 vol% or more and 30 vol% or less, further preferably 0.5 vol% or more and 15 vol% or less, and even more preferably 0.8 vol% or more and 10 vol% or less.

[0612] When the composition according to this embodiment contains (3) a solubility improver (hereinafter also referred to as "component (3)"), regarding the content of component (1) and component (3) in the composition, based on 1 part by mass of component (1), component (3) 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. In addition, component (3) 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, and 20 parts by mass or less. Furthermore, based on 1 part by mass of component (1), the content of component (3) can be 0.1 parts by mass or more and 100 parts by mass or less, 5 parts by mass or more and 60 parts by mass or less, 6 parts by mass or more and 40 parts by mass or less, or 7 parts by mass or more and 20 parts by mass or less. When component (1) contains two or more cyclic peptide compounds, the above ranges refer to its total amount. The same applies to component (3).

[0613] Furthermore, when component (3) is liquid at 25°C, the content of component (3) is preferably 0.05 vol% or more, more preferably 0.075 vol% or more, further preferably 0.1 vol% or more, further preferably 0.2 vol% or more, further preferably 0.3 vol% or more, further preferably 0.5 vol% or more, and further preferably 1.0 vol% or more, based on 100 vol% or less of the liquid component in the composition containing component (3) itself. The content of component (3) is also preferably 100 vol% or less, more preferably 85 vol% or less, further preferably 50 vol% or less, further preferably 40 vol% or less, further preferably 30 vol% or less, further preferably 20 vol% or less, further preferably 15 vol% or less, and further preferably 10 vol% or less. The content of component (3) is preferably 0.05 vol% or more and 50 vol% or less, more preferably 0.3 vol% or more and 30 vol% or less, further preferably 0.5 vol% or more and 15 vol% or less, and even more preferably 0.8 vol% or more and 10 vol% or less.

[0614] The content of component (1) in the composition according to this embodiment can be appropriately set according to the type of cyclic peptide compound, the application of the composition, etc. Examples of the content of component (1) in the composition according to this embodiment are, but not limited to, 0.01 mg / ml or more and 300 mg / ml or less, 0.03 mg / ml or more and 200 mg / ml or less, 0.1 mg / ml or more and 100 mg / ml or less, 0.3 mg / ml or more and 50 mg / ml or less, 1 mg / ml or more and 25 mg / ml or less, 3 mg / ml or more and 10 mg / ml or less per 1 ml of the liquid component contained in the composition according to this embodiment.

[0615] The composition according to this embodiment may also include components in a premixed state of (2) surfactant and (3) solubility improver, such as self-emulsifying drug delivery systems (hereinafter referred to as "SEDDS").

[0616] The compositions according to this embodiment may contain a pharmaceutically acceptable carrier. Examples of carriers include saline, buffered saline, water, isotonic buffer solutions, and combinations thereof.

[0617] Without impairing the effects according to the invention, the compositions according to this embodiment may contain other pharmaceutical components. Examples of other components include excipients, disintegrants, fluidizing agents / lubricants, flavoring agents, stabilizers, preservatives, antioxidants, and binders.

[0618] Examples of excipients include lactose, corn starch, white sugar, glucose, D-mannitol, sorbitol, starch, crystalline cellulose, silicon dioxide, and magnesium aluminum metasilicate.

[0619] Examples of disintegrants include starch, pregelatinized starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium chloride, sodium bicarbonate, calcium citrate, anhydrous silicate, dextrin, pectin, calcium carboxymethyl cellulose, crospopidone, low-substituted hydroxypropyl cellulose, and sodium carboxymethyl starch.

[0620] Examples of fluidizing agents / lubricants include light anhydrous silica, hydrated silica dioxide, magnesium stearate, and talc.

[0621] Examples of flavoring agents include cocoa powder, menthol, aromatic powders, peppermint oil, borneol, and cinnamon powder.

[0622] Examples of stabilizers include phosphatidic acid, ascorbic acid, glycerol, and cetyl alcohol.

[0623] Examples of preservatives include ethylparaben and propylparaben.

[0624] Examples of antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, and propyl gallate.

[0625] Examples of adhesives include sucrose, gelatin, gum arabic powder, and methylcellulose.

[0626] [use]

[0627] The composition according to this embodiment can be used as a composition for promoting the absorption of cyclic peptide compounds because it promotes the oral absorption of cyclic peptide compounds with low membrane permeability.

[0628] The compositions according to this embodiment can also be used as pharmaceutical compositions for challenging targets such as protein-protein interaction inhibitors, agonists, molecular chaperones, etc., depending on the type of cyclic peptide compound used.

[0629] Furthermore, the compositions according to this embodiment can be used as compositions for administration to living organisms, particularly as compositions for oral administration. Examples of subjects to be administered include mammals, particularly mice, rats, rabbits, dogs, monkeys, and humans. The compositions according to this embodiment are particularly suitable for administration to humans. Therefore, the compositions according to the invention can be used as pharmaceutical compositions. Furthermore, the invention provides a method for treatment and / or prevention comprising administering an effective amount of the composition according to the invention to a subject in need.

[0630] [Method for producing the composition]

[0631] The composition according to this embodiment can be produced by a method including the steps (a) and (b):

[0632] (a) Provides a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate, and

[0633] (b) The surfactant, which is a separate component, is mixed with a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate.

[0634] The method for producing the composition according to this embodiment may further include the following step (c):

[0635] (c) The solubility improver is mixed with a compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate. The compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate, the surfactant, and the solubility improver are each as disclosed herein.

[0636] [Other aspects of the invention]

[0637] In a non-limiting aspect, the composition according to this embodiment contains (1) a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof. In this respect, the composition may be used in combination with a surfactant to improve the absorption of the compound according to this embodiment. The composition is not limited to each of the foregoing aspects except that it does not contain a surfactant (i.e., component (2)). When used in combination with a surfactant, the amount of surfactant used 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, based on 1 part by mass of component (1) in the composition according to this embodiment. In addition, the 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, based on 1 part by mass of component (1). Furthermore, based on 1 part by mass of component (1), the amount of surfactant used 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. When component (1) contains two or more cyclic peptide compounds, the above ranges are for their total amounts. The same applies to surfactants.

[0638] In a non-limiting aspect, the present invention can also be considered as a method for improving the absorption of a compound represented by general formula (1), the method comprising incorporating the compound represented by general formula (1), its pharmaceutical salt, or its pharmaceutical solvate, and a surfactant into the same composition. As a specific aspect of the method according to this embodiment, the aspects described in the composition according to the invention can be applied without any particular limitations. Furthermore, in the method according to this embodiment, the surfactant is preferably at least one selected from the group consisting of lauroyl-L-carnitine, sodium octanoate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0639] In a non-limiting aspect, the present invention can also be considered as a method for improving the absorption of a compound represented by general formula (1), the method comprising using a combination of a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof with a surfactant. As a specific aspect of the method according to this embodiment, the aspects described in the compositions according to the invention can be applied without any particular limitations. Furthermore, in the method according to this embodiment, the surfactant is preferably at least one selected from the group consisting of lauroyl-L-carnitine, sodium octanoate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0640] In a non-limiting aspect, the present invention can also be considered as a method for improving the absorption of a compound represented by general formula (1), the method comprising using a combination of a composition containing a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and a composition containing a surfactant. As a specific aspect of the method according to this embodiment, the aspects described in the compositions according to the invention can be applied without any particular limitations. Furthermore, in the method according to this embodiment, the surfactant is preferably at least one selected from the group consisting of lauroyl-L-carnitine, sodium octanoate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)octanoate.

[0641] Example

[0642] The preferred aspects of the present invention are described below by way of examples, but the present invention is not limited thereto.

[0643] [Synthetic Examples] Synthesis of Cyclic Peptide Compounds

[0644] The cyclic peptide compounds CP01 to CP06 (also referred to as compounds CP01 to CP06) shown in Tables 1 and 2 were synthesized by the same method as described in International Publication No. WO 2022 / 234853, and the final product was obtained as a dried product. Specifically, in International Publication No. WO 2022 / 234853, PP1105 corresponds to compound CP01, PP1248 corresponds to compound CP02, PP1275 corresponds to compound CP03, PP1650 corresponds to compound CP04, PP2320 corresponds to compound CP05, and PP2328 corresponds to compound CP06.

[0645] Tables 1 and 2 show the structural formulas of compounds CP01 to CP06, and Table 3 shows the chemical names of compounds CP01 to CP06.

[0646] [Table 1]

[0647]

[0648] [Table 2]

[0649]

[0650] [Table 3]

[0651]

[0652] (Evaluation Example 1) Evaluation of Caco-2 Membrane Permeability

[0653] Caco-2 cells were cultured in 96-well Transwells for 3 weeks. Permeability studies were then initiated by adding 10 μM of compound CP01 to the top side with FaSSIF / HBSS buffer (pH 6.5) containing lauroyl-L-carnitine hydrochloride (manufactured by Sinochem Japan Co., Ltd.), sodium caprylate (manufactured by Sigma-Aldrich Co., Ltd.), or salcaprozate sodium (manufactured by Fluorochem), and adding HBSS buffer (pH 7.4) containing 4% BSA to the bottom side. Each well was shaken at 80 rpm at 37°C with 5% CO2, and samples were taken from the bottom side after 180 minutes of incubation. The permeation amount of the compound was measured by liquid chromatography-mass spectrometry (LC / MS / MS). The permeability coefficient (Caco-2 Papp (cm / sec)) was calculated from the permeation amount. The results are shown in Table 4.

[0654] As a comparative example, permeation was measured using the same procedure as described above, except that a surfactant-free FaSSIF / HBSS buffer (pH 6.5) was used. In other words, compound CP01 and FaSSIF / HBSS buffer (pH 6.5) were added to the top side. The permeability coefficient was calculated from the measured permeation. The results are shown in Table 4.

[0655] [Table 4]

[0656]

[0657] The above results confirm that membrane permeability is improved with the addition of lauroyl-L-carnitine hydrochloride, sodium caprylate, or sodium n-caprylate compared to conditions without these surfactants. In particular, a concentration-dependent improvement in the permeability coefficient was observed with lauroyl-L-carnitine hydrochloride, exhibiting a high permeability coefficient even at low concentrations.

[0658] [Examples 1 to 32, Comparative Examples 1 to 27, and Production Examples 1 to 14] Preparation of absorption-enhancing formulations (1) to (32), solution formulations (1) to (27), and IV formulations (1) to (14)

[0659] Compounds CP01 to CP06, lauroyl-L-carnitine hydrochloride (manufactured by Sinochem Japan Co., Ltd.), water for injection (manufactured by Otsuka Pharmaceutical Factory Co., Ltd.), dimethyl sulfoxide (manufactured by Wako Pure Chemical Co., Ltd.), Cremophor EL (manufactured by Sigma-Aldrich Co., Ltd., Kolliphor EL, generic name: polyoxyethylene castor oil, with an average molar number of ethylene oxide added of 35), Tween 80 (manufactured by Nacalai Tesque, Inc., polyoxyethylene dehydrated sorbitan monooleate), and monkey serum were mixed to form the compositions shown in Tables 5, 6, and 7 to prepare absorption-enhancing formulations (1) to (32), solution formulations (1) to (27), and IV formulations (1) to (14). It should be noted that compounds CP01 to CP06 were mixed while dissolved in dimethyl sulfoxide. Additionally, lauroyl-L-carnitine hydrochloride, Cremophor EL, and Tween 80 are added and mixed in powder or undiluted solution form.

[0660] In Tables 5, 6 and 7, (*1) indicates the content in 1 mL of solvent, and (*2) indicates the content based on 100 volume% of the solvent.

[0661] [Table 5]

[0662]

[0663] [Table 6]

[0664]

[0665] [Table 7]

[0666]

[0667] (Evaluation Example 2) Mouse PK Study (3 mg / kg, 100 mg / kg)

[0668] The pharmacokinetics of the solutions (1) and (2) prepared in Comparative Examples 1 and 2, and the absorption enhancers (1) and (2) prepared in Examples 1 and 2, after oral administration were evaluated in mice. Female mice (Balb / c nu-nu, 7 weeks old, manufactured by Charles River Laboratories Japan, Inc.: 3 mice per group) were orally administered either the solution (1) prepared in Comparative Example 1 or the absorption enhancer (1) prepared in Example 1 at a dose of 3 mg / kg compound CP01, and blood was collected over time from the jugular vein using a syringe for up to 24 hours after administration. Alternatively, the solution (2) prepared in Comparative Example 2 or the absorption enhancer (2) prepared in Example 2 at a dose of 100 mg / kg compound CP01 was orally administered, and blood was collected over time from the jugular vein using a syringe for up to 24 hours after administration. In addition, the intravenous formulation (1) prepared in Production Example 1 was administered at a dose of 1 mg / kg of compound CP01, and blood was collected over time from the jugular vein using a syringe for up to 24 hours after administration. The blood was dispensed into tubes treated with heparin as an anticoagulant and centrifuged to separate the plasma. After deproteinization with acetonitrile, the plasma concentration of compound CP01 was measured using an LC / MS / MS apparatus (XEVO TQ-XS manufactured by Waters Corporation). Based on the obtained changes in plasma concentration, pharmacokinetic parameters were calculated using non-compartmental analysis with the analytical software Phoenix WinNonlin 8.2 (manufactured by Certara LP). The results are shown in Table 8.

[0669] As pharmacokinetic parameters, the area under the plasma concentration-time curve (AUC; ng·h / mL), the peak plasma concentration after oral administration (Cmax; ng / mL), and bioavailability (BA) were calculated. Concentrations equal to or below the lower limit of quantitation were considered to be 0 ng / mL. BA was calculated as the ratio of the AUC of the solution formulation (AUCsol) or the AUC of the absorption enhancer formulation (AUClc) to the AUC of the IV formulation (AUCiv), i.e., AUCsol / AUCiv or AUCClc / AUCiv. In compound CP01, it was confirmed that any AUC in the administration group of the absorption enhancer formulation (1) or (2) of Examples 1 or 2 was higher than the AUC in the administration group of the solution formulation (1) or (2) of Comparative Examples 1 or 2, and an increase in Cmax was also observed (Table 8). This confirms that compounds with low membrane permeability exhibit high BA when lauroyl-L-carnitine hydrochloride is used compared to compounds without lauroyl-L-carnitine hydrochloride.

[0670] [Table 8]

[0671]

[0672] (Evaluation Example 3) Mouse PK Study (3 mg / kg, 100 mg / kg)

[0673] The pharmacokinetics of the solution formulations (3) and (4) prepared in Comparative Examples 3 and 4, and the absorption enhancers (3) and (4) prepared in Examples 3 and 4, and the intravenous administration of the IV formulation (2) prepared in Production Example 2 were evaluated in female mice (Balb / c nu-nu, 7 weeks old) following oral administration, as well as the intravenous administration of the IV formulation (2) prepared in Production Example 2, based on the resulting changes in plasma concentrations. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2. The results are shown in Table 9. The results confirmed that any AUC in the administration groups of the absorption enhancers (3) or (4) of Examples 3 or 4 was higher than that in the administration groups of the solution formulations (3) or (4) of Comparative Examples 3 or 4, and an increase in Cmax was also observed (Table 9). This confirmed that the use of lauroyl-L-carnitine hydrochloride exhibited a higher BA compared to the use of lauroyl-L-carnitine hydrochloride.

[0674] [Table 9]

[0675]

[0676] (Evaluation Example 4) Mouse PK Study (3 mg / kg, 100 mg / kg)

[0677] The pharmacokinetics of the solution formulations (5) and (6) prepared in Comparative Examples 5 and 6, and the absorption-enhancing formulations (5) and (6) prepared in Examples 5 and 6, and the intravenous administration of the IV formulation (3) prepared in Production Example 3, were evaluated in female mice (Balb / c nu-nu, 7 weeks old) following oral administration, as in Evaluation Example 2. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 10. The results confirmed that any AUC in the administration groups of the absorption-enhancing formulations (5) or (6) of Examples 5 or 6 was higher than that in the administration groups of the solution formulations (5) or (6) of Comparative Examples 5 or 6, and an increase in Cmax was also observed (Table 10). This confirms that the use of lauroyl-L-carnitine hydrochloride exhibits a higher BA compared to the use without lauroyl-L-carnitine hydrochloride.

[0678] [Table 10]

[0679]

[0680] (Evaluation Example 5) Mouse PK Study (3 mg / kg, 30 mg / kg)

[0681] Pharmacokinetics of the solutions (7) and (8) prepared in Comparative Examples 7 and 8, and the absorption enhancers (7) and (8) prepared in Examples 7 and 8, and the intravenous administration of the IV formulation (4) prepared in Production Example 4, were evaluated in male mice (C57BL6J, 10 weeks old, manufactured by The Jackson Laboratory Japan, Inc.: 3 mice per group) after oral administration, as well as the IV formulation (4) prepared in Production Example 4, after intravenous administration, based on the resulting changes in plasma concentrations. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2. The results are shown in Table 11. The results confirmed that any AUC in the administration groups of the absorption enhancers (7) or (8) of Examples 7 or 8 was higher than that in the administration groups of the solutions (7) or (8) of Comparative Examples 7 or 8, and an increase in Cmax was also observed (Table 11). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0682] [Table 11]

[0683]

[0684] (Evaluation Example 6) Mouse PK Study (3 mg / kg, 30 mg / kg)

[0685] The pharmacokinetics of the solution formulations (9) and (10) prepared in Comparative Examples 9 and 10, and the absorption-enhancing formulations (9) and (10) prepared in Examples 9 and 10, and the intravenous administration of the IV formulation (5) prepared in Production Example 5, were evaluated in male mice (C57BL6J, 10 weeks old) following oral administration, as well as the IV formulation (5) prepared in Production Example 5. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2, based on the resulting changes in plasma concentrations. The results are shown in Table 12. The results confirmed that any AUC in the administration groups of the absorption-enhancing formulations (9) or (10) of Examples 9 or 10 was higher than that in the administration groups of the solution formulations (9) or (10) of Comparative Examples 9 or 10, and an increase in Cmax was also observed (Table 12). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0686] [Table 12]

[0687]

[0688] (Evaluation Example 7) Mouse PK Study (3 mg / kg, 30 mg / kg)

[0689] The pharmacokinetics of the solution formulations (11) and (12) prepared in Comparative Examples 11 and 12, and the absorption enhancers (11) and (12) prepared in Examples 11 and 12, and the intravenous administration of the IV formulation (6) prepared in Production Example 6 were evaluated in male mice (C57BL6J, 10 weeks old) following oral administration. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 13. The results confirmed that any AUC in the administration groups of the absorption enhancers (11) or (12) of Examples 11 or 12 was higher than that in the administration groups of the solution formulations (11) or (12) of Comparative Examples 11 or 12, and an increase in Cmax was also observed (Table 13). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0690] [Table 13]

[0691]

[0692] (Evaluation Example 8) Rat PK Study (3 mg / kg, 30 mg / kg)

[0693] Pharmacokinetics of the solutions (13) and (14) prepared in Comparative Examples 13 and 14, and the absorption enhancers (13) and (14) prepared in Examples 13 and 14, and the IV formulation (7) prepared in Production Example 7, were evaluated in the same manner as in Evaluation Example 2, following oral administration in male rats (SD, 6 weeks old, manufactured by The Jackson Laboratory Japan, Inc.: 3 rats per group). Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 14. The results confirmed that any AUC in the administration groups of the absorption enhancers (13) or (14) of Examples 13 or 14 was higher than that in the administration groups of the solutions (13) or (14) of Comparative Examples 13 or 14, and an increase in Cmax was also observed (Table 14). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0694] [Table 14]

[0695]

[0696] (Evaluation Example 9) Rat PK Study (3 mg / kg, 30 mg / kg)

[0697] The pharmacokinetics of the solutions (15) and (16) prepared in Comparative Examples 15 and 16, and the absorption enhancers (15) and (16) prepared in Examples 15 and 16, and the intravenous administration of the IV formulation (8) prepared in Production Example 8, were evaluated in male rats (SD, 6 weeks old) following oral administration, in the same manner as in Evaluation Example 2. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 15. The results confirmed that any AUC in the administration groups of the absorption enhancers (15) or (16) of Examples 15 or 16 was higher than that in the administration groups of the solutions (15) or (16) of Comparative Examples 15 or 16, and an increase in Cmax was also observed (Table 15). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0698] [Table 15]

[0699]

[0700] (Evaluation Example 10) Rat PK Study (3 mg / kg, 30 mg / kg)

[0701] The pharmacokinetics of the solutions (17) and (18) prepared in Comparative Examples 17 and 18, and the absorption enhancers (17) and (18) prepared in Examples 17 and 18, and the intravenous administration of the IV formulation (9) prepared in Production Example 9, were evaluated in male rats (SD, 6 weeks old) following oral administration, in the same manner as in Evaluation Example 2. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 16. The results confirmed that any AUC in the administration groups of the absorption enhancers (17) or (18) of Examples 17 or 18 was higher than that in the administration groups of the solutions (17) or (18) of Comparative Examples 17 or 18, and an increase in Cmax was also observed (Table 16). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0702] [Table 16]

[0703]

[0704] (Evaluation Example 11) Rat PK Study (3 mg / kg, 30 mg / kg)

[0705] Pharmacokinetics of the solutions (19) and (20) prepared in Comparative Examples 19 and 20, and the absorption enhancers (19) and (20) prepared in Examples 19 and 20, and the intravenous administration of the IV formulation (10) prepared in Production Example 10, were evaluated in male rats (SD, 7 weeks old, The Jackson Laboratory Japan, Inc.: 3 rats per group) after oral administration, as well as the IV formulation (10) prepared in Production Example 10 after intravenous administration, based on the resulting changes in plasma concentrations. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2. The results are shown in Table 17. The results confirmed that any AUC in the administration groups of the absorption enhancers (19) or (20) of Examples 19 or 20 was higher than that in the administration groups of the solutions (19) or (20) of Comparative Examples 19 or 20, and an increase in Cmax was also observed (Table 17). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0706] [Table 17]

[0707]

[0708] (Evaluation Example 12) Rat PK Study (3 mg / kg, 30 mg / kg)

[0709] The pharmacokinetics of the solutions (21) and (22) prepared in Comparative Examples 21 and 22, and the absorption enhancers (21) and (22) prepared in Examples 21 and 22, and the intravenous administration of the IV formulation (11) prepared in Production Example 11, were evaluated in male rats (SD, 7 weeks old) following oral administration, as well as the IV formulation (11) prepared in Production Example 11. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2, based on the resulting changes in plasma concentrations. The results are shown in Table 18. The results confirmed that any AUC in the administration groups of the absorption enhancers (21) or (22) of Examples 21 or 22 was higher than that in the administration groups of the solutions (21) or (22) of Comparative Examples 21 or 22, and an increase in Cmax was also observed (Table 18). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0710] [Table 18]

[0711]

[0712] (Evaluation Example 13) Rat PK Study (3 mg / kg, 30 mg / kg)

[0713] The pharmacokinetics of the solutions (23) and (24) prepared in Comparative Examples 23 and 24, and the absorption enhancers (23) and (24) prepared in Examples 23 and 24, and the intravenous administration of the IV formulation (12) prepared in Production Example 12 were evaluated in male rats (SD, 7 weeks old) following oral administration, as well as the IV formulation (12) prepared in Production Example 12 following intravenous administration. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2, based on the resulting changes in plasma concentrations. The results are shown in Table 19. The results confirmed that any AUC in the administration groups of the absorption enhancers (23) or (24) of Examples 23 or 24 was higher than that in the administration groups of the solutions (23) or (24) of Comparative Examples 23 or 24, and an increase in Cmax was also observed (Table 19). This confirms that the use of lauroyl-L-carnitine hydrochloride resulted in higher BA levels compared to the use of lauroyl-L-carnitine hydrochloride.

[0714] [Table 19]

[0715]

[0716] (Evaluation Example 14) Monkey PK Study (1 mg / kg, 3 mg / kg)

[0717] The pharmacokinetics of the solution formulations (25) and (26) prepared in Comparative Examples 25 and 26, and the absorption-enhancing formulations (25) through (30) prepared in Examples 25 and 30, and the intravenous administration of the IV formulation (13) prepared in Production Example 13, were evaluated in male cynomolgus monkeys (manufactured by Tian Hu Cambodia Animal Breeding Research Center: 4 monkeys per group) after oral administration, as well as in Production Example 13 after intravenous administration, in the same manner as in Evaluation Example 2, except that blood was collected from the femoral vein over time using a syringe treated with heparin as an anticoagulant. Based on the resulting changes in plasma concentration, pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2. The results are shown in Table 20. The results confirmed that the AUC of any of the absorption-enhancing formulations (25) to (27) or (28) to (30) in Examples 25 to 27 or 28 to 30 was higher than that in the application group of the solution formulations (25) or (26) in Comparative Examples 25 or 26, and an increase in Cmax was also observed (Table 20). This confirms that the use of lauroyl-L-carnitine hydrochloride exhibits a higher BA compared to the use of lauroyl-L-carnitine hydrochloride.

[0718] [Table 20]

[0719]

[0720] (Evaluation Case 15) Monkey PK Study (3 mg / kg)

[0721] The pharmacokinetics of the solution formulation (27) prepared in Comparative Example 27 and the absorption enhancers (31) and (32) prepared in Examples 31 and 32, and the intravenous administration of the IV formulation (14) prepared in Production Example 14, in male cynomolgus monkeys were evaluated in the same manner as in Evaluation Example 2. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 21. The results confirmed that any AUC in the administration groups of the absorption enhancers (31) and (32) of Examples 31 and 32 was higher than that in the administration group of the solution formulation (27) of Comparative Example 27, and an increase in Cmax was also observed (Table 21). This confirms that the use of lauroyl-L-carnitine hydrochloride exhibits a higher BA compared to the absence of lauroyl-L-carnitine hydrochloride.

[0722] [Table 21]

[0723]

[0724] [Example 33] Preparation of a formulation (1) containing a solid dispersion

[0725] Compound CP01 and HPMCAS (manufactured by Shin-Etsu Chemical Co., Ltd.) were added to acetone such that the quantitative ratio of CP01 to HPMCAS was 1:2 and the solid concentration was 12 wt / vol%, thereby preparing a suspension. The suspension was spray-dried to obtain a solid dispersion. The solid dispersion was mixed with sodium lauryl sulfate (manufactured by BASF) at a quantitative ratio of 9:5 to prepare a formulation containing the solid dispersion (1).

[0726] (Evaluation Case 16) Monkey PK Study (3 mg / kg)

[0727] The pharmacokinetics of the combination of oral administration of the solution formulation (26) prepared in Comparative Example 26, followed by oral administration of a combination of capsules filled with the solid dispersion formulation (1) prepared in Example 33 and capsules filled with lauroyl-L-carnitine hydrochloride (10 mg / kg) and intravenous administration of the IV formulation (13) prepared in Production Example 13 in male cynomolgus monkeys were evaluated in the same manner as in Evaluation Example 2. Pharmacokinetic parameters were calculated using the same analysis as in Evaluation Example 2 based on the resulting changes in plasma concentrations. The results are shown in Table 22. The results confirmed that the AUC in the combination administration group of capsules filled with the solid dispersion formulation (1) prepared in Example 33 and capsules filled with lauroyl-L-carnitine hydrochloride (10 mg / kg) was higher than that in the administration group of the solution formulation (26) in Comparative Example 26, and an increase in Cmax was also observed (Table 22). This confirms that when mixed with sodium lauryl sulfate and further combined with lauroyl-L-carnitine hydrochloride, it exhibits high BA levels.

[0728] [Table 22]

[0729]

Claims

1. A composition comprising a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof, and a surfactant. The surfactant is represented by any one of the following general formulas (a1) to (a3): [Formula 1] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl and a C1 to C6 alkyl;] P1 is a C1 to C6 alkyl group; R2 is a C1 to C6 alkyl group; R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle. Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P4 is a C1 to C6 alkyl group; R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl and C3 to C8 cycloalkyl; P6 is a C1 to C6 alkyl group; R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; R8 together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8 form a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group. R9 together with Q9 and the carbon atoms bonded to R9 and Q9 form a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups; P9 is hydrogen or a C1 to C6 alkyl group; R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P 10 It is a C1 to C6 alkyl group; R 11 It is a di-C1 to C6 alkylamino carbonyl or a 4- to 8-membered cyclic amino carbonyl; and P 11 [C1 to C6 alkyl], [Equation 2] [Formula 3] [Formula 4] [where R] S1 [This indicates a saturated or unsaturated straight-chain hydrocarbon group having 5 or more and 13 or fewer carbon atoms, which may have substituents; X represents sodium or potassium; and Y represents a group represented by formula (a4) or a stereoisomer thereof.] [Formula 5] [in [Formula 6] (Represents key).

2. A composition for use in combination with a surfactant, The surfactant described herein is represented by any one of the following general formulas (a1) to (a3). The composition comprises a compound represented by general formula (1), a pharmaceutical salt thereof, or a pharmaceutical solvate thereof: [Formula 7] [Formula 8] [Formula 9] [where R] S1 [This indicates a saturated or unsaturated straight-chain hydrocarbon group having 5 or more and 13 or fewer carbon atoms, which may have substituents; X represents sodium or potassium; and Y represents a group represented by formula (a4) or a stereoisomer thereof.] [Formula 10] [in [Equation 11] [Representation key], [Equation 12] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl and a C1 to C6 alkyl;] P1 is a C1 to C6 alkyl group; R2 is a C1 to C6 alkyl group; R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle. Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P4 is a C1 to C6 alkyl group; R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl and C3 to C8 cycloalkyl; P6 is a C1 to C6 alkyl group; R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; R8 together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8 form a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group. R9 together with Q9 and the carbon atoms bonded to R9 and Q9 form a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups; P9 is hydrogen or a C1 to C6 alkyl group; R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P 10 It is a C1 to C6 alkyl group; R 11 It is a di-C1 to C6 alkylamino carbonyl or a 4- to 8-membered cyclic amino carbonyl; and P 11 (C1 to C6 alkyl).

3. The composition according to claim 1 or 2, wherein the surfactant is acylcarnitine.

4. The composition according to claim 1 or 2, wherein the surfactant is an alkyl carboxylate.

5. The composition according to claim 1 or 2, wherein the surfactant is N-(8-[2-hydroxybenzoyl]amino)octanoate.

6. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1a). [Equation 13] 7. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1b). [Formula 14] 8. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1c). [Formula 15] 9. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1d). [Formula 16] 10. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1e). [Equation 17] 11. The composition according to any one of claims 1 to 5, wherein the compound represented by general formula (1) is a compound represented by formula (1f). [Formula 18] 12. The composition according to any one of claims 1 to 11, further comprising a solubility improver.

13. The composition of claim 12, wherein the solubility improver comprises a polymer that forms a solid dispersion with the compound.

14. The composition according to any one of claims 1 to 13, wherein the bioavailability (BA) value of the compound measured in a system containing the surfactant is 1.1 times or greater than the value measured in a system without the surfactant.

15. A method for improving the absorption of compounds represented by general formula (1), The method comprises incorporating a compound represented by general formula (1), its pharmaceutical salt, or a pharmaceutical solvate thereof, and a surfactant selected from the group consisting of lauroyl-L-carnitine, sodium caprylate, sodium lauryl sulfate, and sodium N-(8-[2-hydroxybenzoyl]amino)caprylate into the same composition: [Formula 19] [Where R1 is a C1 to C6 alkyl, or a C3 to C8 cycloalkyl and a C1 to C6 alkyl;] P1 is a C1 to C6 alkyl group; R2 is a C1 to C6 alkyl group; R3 is hydrogen, or together with P3 and the carbon atom bonded to R3 and the nitrogen atom bonded to P3, it forms a 4- to 7-membered saturated heterocycle. Except when R3 and P3 form a 4- to 7-membered saturated heterocycle, P3 is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P4 is a C1 to C6 alkyl group; R5 is a benzyl group optionally substituted with one or more groups selected from the group consisting of: C1 to C6 alkyl, C1 to C6 haloalkyl and C3 to C8 cycloalkyl; P6 is a C1 to C6 alkyl group; R7 is a phenethyl group optionally substituted with one or more groups selected from the group consisting of: halogen, C1 to C6 haloalkyl and C1 to C6 alkoxy; R8 together with P8, the carbon atom bonded to R8, and the nitrogen atom bonded to P8 form a 4- to 7-membered saturated heterocycle, wherein the 4- to 7-membered saturated heterocycle is optionally substituted with a C1 to C6 alkoxy group. R9 together with Q9 and the carbon atoms bonded to R9 and Q9 form a 3- to 8-membered alicyclic ring, wherein the 3- to 8-membered alicyclic ring is optionally substituted with one or more C1 to C6 alkyl groups; P9 is hydrogen or a C1 to C6 alkyl group; R 10 It is a C1 to C6 alkyl or a C3 to C8 cycloalkyl; P 10 It is a C1 to C6 alkyl group; R 11 It is a di-C1 to C6 alkylamino carbonyl or a 4- to 8-membered cyclic amino carbonyl; and P 11 (C1 to C6 alkyl).

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