Peptide, surfactant having sugar fatty acid ester structure, and pharmaceutical composition containing (METH)acrylic acid-based polymer

Abstract

The present invention provides a solid dispersion containing therein: (1) a peptide; (2) a surfactant having a sugar fatty acid ester structure; and (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl ester, (meth)acrylic acid alkyl amino alkyl ester, and (meth)acrylic acid ammonio alkyl ester. The content of the polymer with respect to the content of the peptide is 0.6-20.0 in terms of weight ratio.

Description

Pharmaceutical composition comprising a peptide, a surfactant having a sugar fatty acid ester structure, and a (meth)acrylic acid-based polymer

[0001] The present invention relates to a pharmaceutical composition comprising a peptide, a surfactant having a sugar fatty acid ester structure, and a (meth)acrylic acid-based polymer.

[0002] In recent years, the development of drug discovery technologies that use medium-molecular-weight compounds (e.g., molecular weights of 500 to 2000) to enable drug discovery for tough targets, such as protein-protein interaction inhibitors, agonists, and molecular chaperones, has been attracting attention (Non-Patent Document 1).

[0003] One of the factors that affect the therapeutic effect of a pharmaceutical composition is the solubility of the administered active ingredient in the body. In particular, peptides, which are medium-sized molecules that have recently attracted attention in the development of drug discovery technology, are known to have significantly different solubility in aqueous media such as body fluids depending on the type and number of amino acid residues they contain.

[0004] Patent Document 1: JP 2001-302538 A, US Patent Application Publication No. 2017 / 0252332, International Publication No. 2023 / 249087, International Publication No. 2007 / 047948, International Publication No. 2005 / 105050

[0005] Satyanarayanajois, SD, Hill, RA Medicinal chemistry for 2020, Future Med. Chem. 2011, 3, 1765-1786

[0006] Therefore, an object of the present invention is to provide a preparation that can significantly improve the solubility of a peptide.

[0007] The present invention relates to, for example, the following:

[0008] [1] A solid dispersion comprising (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, and (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester, wherein the weight ratio of the content of the polymer to the content of the peptide is 0.6 to 20.0. [2] A method for producing a solid dispersion comprising (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester, and (4) a solvent, wherein the weight ratio of the content of the polymer to the content of the peptide is 0.6 to 20.0. [3] The method for producing a solid dispersion according to [2], wherein the solvent is removed by spray drying. [4] A solid dispersion produced by the production method according to [2] or [3]. [5] The solid dispersion or method for producing a solid dispersion according to any one of [1] to [4], wherein the molecular weight of the peptide is from 500 g / mol to 5,000 g / mol. [6] The solid dispersion or method for producing a solid dispersion according to any one of [1] to [5], wherein the number of amino acid residues constituting the peptide is from 5 to 30. [7] The solid dispersion or method for producing a solid dispersion according to any one of [1] to [6], wherein the peptide has a cyclic portion. [8] The solid dispersion or method for producing a solid dispersion according to any one of [1] to [7], wherein the number of amino acid residues constituting the cyclic portion is from 5 to 15. [9] The solid dispersion or method for producing a solid dispersion according to any one of [1] to [8], wherein the cyclic portion consists of a 28- to 55-membered ring.

[10] The solid dispersion or the method for producing a solid dispersion according to any one of [1] to [9], wherein the peptide comprises one or more N-substituted amino acid residues.

[11] The solid dispersion or the method for producing a solid dispersion according to any one of [1] to

[10] , wherein the peptide comprises three or more N-substituted amino acid residues.

[12] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[11] , wherein the peptide comprises 4 or more N-substituted amino acid residues.

[13] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[12] , wherein the peptide comprises 5 or more N-substituted amino acid residues.

[14] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[13] , wherein the peptide comprises 6 or more N-substituted amino acid residues.

[15] The nitrogen atom constituting the main chain of the N-substituted amino acid is C. １ -C ６ is substituted with alkyl, １ -C ６

[16] The solid dispersion or method for producing a solid dispersion according to any one of

[10] to

[14] , wherein the alkyl optionally forms a ring together with the carbon atom bonded to the nitrogen atom and the nitrogen atom.

[17] The solid dispersion or method for producing a solid dispersion according to any one of

[10] to

[14] , wherein the N-substituted amino acid is an N-methyl amino acid or an N-ethyl amino acid.

[18] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[17] , wherein the peptide comprises at least one β-amino acid skeleton.

[19] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[18] , wherein the peptide comprises at least one β-amino acid skeleton in the cyclic portion.

[20] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[19] , wherein the peptide comprises one or more N-unsubstituted amino acid residues.

[21] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[20] , wherein the peptide does not have an indolyl group.

[22] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[21] , wherein the peptide does not have a substituted or unsubstituted hydroxyphenyl group.

[23] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[22] , wherein the peptide comprises 0 to 3 aromatic rings.

[24] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[23] , wherein the peptide has a ClogP of 4 or more and 25 or less.

[25] The solid dispersion or the method for producing the solid dispersion according to any one of [1] to

[24] , wherein the ClogP of the peptide is equal to or greater than the ClogP value of peptide (CP02) shown below.

[26] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[25] , wherein the value of ClogP / number of amino acid residues of the peptide is 1.0 or more and 1.8 or less.

[27] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[26] , wherein the surfactant is a nonionic surfactant.

[28] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[27] , wherein the HLB value of the surfactant is 1 to 20.

[29] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[28] , wherein the surfactant has a disaccharide residue.

[30] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[29] , wherein the surfactant has a sucrose residue.

[31] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[30] , wherein the surfactant is a sucrose fatty acid ester.

[32] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[31] , wherein the surfactant is a sucrose mixed fatty acid ester.

[33] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[32] , wherein the ester composition of the surfactant comprises at least one selected from the group consisting of monoesters, diesters, and triesters.

[34] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[33] , wherein the ester composition of the surfactant comprises at least one selected from the group consisting of monoesters and diesters.

[35] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[34] , wherein the ester composition of the surfactant comprises monoesters and diesters.

[36] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[35] , wherein the proportion of monoesters in the ester composition of the surfactant is 80 wt% or more.

[37] The solid dispersion or the method for producing a solid dispersion according to any one of [1] to

[36] , wherein the proportion of monoester in the ester composition of the surfactant is 90 wt % or more.

[38] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[37] , wherein the proportion of monoester in the ester composition of the surfactant is 95% by weight or more.

[39] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[38] , wherein the proportion of monoester in the ester composition of the surfactant is 98% by weight or more.

[40] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[39] , wherein the number of carbon atoms contained in the fatty acid moiety of the surfactant is 14 to 20.

[41] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[40] , wherein the fatty acid composition of the surfactant comprises at least one selected from the group consisting of palmitic acid and stearic acid.

[42] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[41] , wherein the fatty acid composition of the surfactant comprises palmitic acid and stearic acid.

[43] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[42] , wherein the proportion of stearic acid in the fatty acid composition of the surfactant is 10% by weight or more.

[44] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[43] , wherein the proportion of stearic acid in the fatty acid composition of the surfactant is 20% by weight or more.

[45] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[44] , wherein the proportion of stearic acid in the fatty acid composition of the surfactant is 30% by weight or more.

[46] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[45] , wherein the proportion of stearic acid in the fatty acid composition of the surfactant is 50% by weight or more.

[47] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[46] , wherein the polymer is an ionic polymer.

[48] ​​The solid dispersion or the method for producing a solid dispersion according to any one of [1] to

[47] , wherein the polymer is anionic.

[49] The solid dispersion or the method for producing a solid dispersion according to any one of [1] to

[48] , wherein the molecular weight of the polymer is 10,000 g / mol or more and 10,000,000 g / mol or less.

[50] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[49] , wherein the polymer is a polymer made of a (meth)acrylic acid alkyl ester or a copolymer containing at least two selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

[51] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[50] , wherein the polymer is a copolymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonio alkyl ester, and a (meth)acrylic acid alkyl ester.

[52] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[51] , wherein the polymer is a copolymer containing at least one selected from the group consisting of (meth)acrylic acid, and a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid alkyl ester.

[53] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[52] , wherein the polymer is a copolymer containing an alkyl (meth)acrylate and (meth)acrylic acid.

[54] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[53] , wherein the polymer is a copolymer containing at least one selected from the group consisting of methyl methacrylate and ethyl acrylate and (meth)acrylic acid.

[55] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[54] , wherein the polymer is a copolymer containing at least one selected from the group consisting of methyl methacrylate and ethyl acrylate and methacrylic acid.

[56] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[55] , wherein the polymer is a copolymer containing methyl methacrylate and methacrylic acid.

[57] The solid dispersion or the method for producing a solid dispersion according to any one of [2] to

[56] , wherein the solvent is at least one selected from the group consisting of water, an alcohol, a ketone, an ester, acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran.

[58] The solid dispersion or the method for producing a solid dispersion according to

[57] , wherein the alcohol is at least one selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, and butanol.

[59] The solid dispersion or the method for producing a solid dispersion according to

[57] or

[58] , wherein the ketone is at least one selected from the group consisting of acetone, methyl ethyl ketone, and methyl isobutyl ketone.

[60] The solid dispersion or the method for producing a solid dispersion according to any one of

[57] to

[59] , wherein the ester is at least one selected from the group consisting of ethyl acetate and propyl acetate.

[61] The solid dispersion or method for producing a solid dispersion according to any one of

[57] to

[60] , wherein the solvent is water.

[62] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[61] , wherein the ratio of the content of the surfactant to the content of the peptide is 0.1 to 15.0 by weight.

[63] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[62] , wherein the ratio of the content of the polymer to the content of the surfactant is 1.0 to 15.0 by weight.

[64] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[63] , wherein the total weight of the peptide, the surfactant, and the polymer contained in the solid dispersion accounts for 95% or more of the total weight of the solid dispersion.

[65] The solid dispersion or method for producing a solid dispersion according to any one of [1] to

[64] , wherein the solid dispersion is a composition for improving the solubility of the peptide.

[66] A pharmaceutical composition comprising the solid dispersion according to any one of [1] to

[65] .

[67] The pharmaceutical composition according to

[66] , wherein the peptide is an active ingredient.

[0009] According to the present invention, a formulation capable of significantly improving the solubility of a peptide can be provided. The composition according to the present invention is suitable for oral administration.

[0010] 1 is a graph showing the solubility of FaSSIF after adding it to the solid dispersions obtained in each Example, Comparative Example, and Reference Example and shaking for a predetermined period of time.

[0011] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0012] As used herein, "one or more" means one or more than one. When "one or more" is used in the context of substituents on a group, the term means a number from one to the maximum number of substituents permitted by that group. Specific examples of "one or more" include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and / or more.

[0013] In this specification, the term "to" indicating a range includes both ends of the range. For example, "A to B" means a range equal to or greater than A and equal to or less than B.

[0014] As used herein, the term "about" when used in conjunction with a numerical value means a range of values ​​of plus and minus 10% of that numerical value.

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

[0016] In this specification, the term "(meth)acrylic acid" means acrylic acid, methacrylic acid, or both acrylic acid and methacrylic acid. Similar expressions in this specification are to be interpreted in the same manner.

[0017] In this specification, "wt / vol %" represents weight / volume %.

[0018] The composition according to this embodiment is a solid dispersion containing (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, and (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester, wherein the weight ratio of the content of the polymer to the content of the peptide is 0.6 or more and 20.0 or less. The composition according to this embodiment is preferably a pharmaceutical composition.

[0019] In this specification, for convenience, a "polymer comprising at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester" may be simply referred to as a "polymer."

[0020] [Peptide] As used herein, the term "peptide" is not particularly limited as long as it is a peptide formed by amide bonds or ester bonds between natural amino acids and / or unnatural amino acids. As used herein, the "amino acid residues" that constitute a peptide may be simply referred to as "amino acids."

[0021] The molecular weight of the peptide in this embodiment is not particularly limited, and may be, for example, 500 g / mol or more, 550 g / mol or more, 600 g / mol or more, 650 g / mol or more, 700 g / mol or more, 750 g / mol or more, 800 g / mol or more, 850 g / mol or more, 900 g / mol or more, 950 g / mol or more, 1,000 g / mol or more, 1,100 g / mol or more, 1, It may be 200 g / mol or more, 1,300 g / mol or more, or 1,400 g / mol or more, and may be 5,000 g / mol or less, 4,000 g / mol or less, 3,000 g / mol or less, 2,500 g / mol or less, 2,000 g / mol or less, 1,900 g / mol or less, 1,800 g / mol or less, 1,700 g / mol or less, or 1,600 g / mol or less. The molecular weight of the peptide in this embodiment is not particularly limited, and may be, for example, 500 g / mol to 5,000 g / mol, 700 g / mol to 4,000 g / mol, 800 g / mol to 3,000 g / mol, 900 g / mol to 2,500 g / mol, 1,000 g / mol to 2,000 g / mol, 1,200 g / mol to 1,900 g / mol, 1,300 g / mol to 1,800 g / mol, or 1,400 g / mol to 1,600 g / mol. The molecular weight of the peptide in this embodiment is not particularly limited, but is, for example, 500 g / mol to 5,000 g / mol, preferably 1,000 g / mol to 2,000 g / mol, more preferably 1,300 g / mol to 1,800 g / mol, and most preferably 1,400 g / mol to 1,600 g / mol. The molecular weight herein refers to the sum of the atomic weights of the atoms constituting the compound molecule (unit: g / mol), and is obtained by calculating the sum of the atomic weights of the atoms contained in the molecular structure (unit: g / mol). In this specification, the molecular weight unit may be omitted.

[0022] As used herein, the terms "number of amino acids" and "number of amino acid residues" refer to the number of amino acid residues (amino acid units) constituting a peptide, and refer to the number of amino acid units generated when the amide bonds, ester bonds, and cyclized bond linking the amino acids are cleaved. For example, the number of amino acids and the number of amino acid residues in a cyclic peptide consisting of 10 amino acid residues and 1 amino acid residue in a linear portion are 11.

[0023] The number of amino acid residues constituting the peptide in this embodiment is not particularly limited, and may be, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more, or 30 or less, 25 or less, 20 or less, 17 or less, 15 or less, 14 or less, 13 or less, 12 or less, or 11 or less. The number of amino acid residues constituting the peptide in this embodiment is not particularly limited, and may be, for example, 5 or more and 30 or less, 6 or more and 25 or less, 7 or more and 20 or less, 8 or more and 17 or less, 9 or more and 15 or less, 10 or more and 14 or less, 11 or more and 13 or less, 11 or more and 12 or less, or 11. The number of amino acid residues constituting the peptide in this embodiment is not particularly limited, and may be, for example, 5 or more and 30 or less, preferably 9 or more and 15 or less, more preferably 11 or more and 13 or less, and most preferably 11.

[0024] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). Also, as used herein, "amino acid residue" includes natural amino acid residues and unnatural amino acid (amino acid derivative) residues.

[0025] Naturally occurring amino acids refer to glycine (Gly), L-alanine (Ala), L-serine (Ser), L-threonine (Thr), L-valine (Val), L-leucine (Leu), L-isoleucine (Ile), L-phenylalanine (Phe), L-tyrosine (Tyr), L-tryptophan (Trp), L-histidine (His), L-glutamic acid (Glu), L-aspartic acid (Asp), L-glutamine (Gln), L-asparagine (Asn), L-cysteine ​​(Cys), L-methionine (Met), L-lysine (Lys), L-arginine (Arg), and L-proline (Pro).

[0026] Examples of unnatural amino acids (amino acid derivatives) include, but are not limited to, β-amino acids, D-amino acids, N-substituted amino acids (excluding Pro), α,α-disubstituted amino acids, amino acids whose side chains differ from those of natural amino acids, hydroxycarboxylic acids, etc. As used herein, unnatural N-substituted amino acids refer to N-substituted amino acids other than Pro.

[0027] As used herein, amino acids may have any steric configuration. The side chain of an amino acid is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a heteroaralkyl group, a cycloalkyl group, or a spiro-linked cycloalkyl group. Each of these groups may be substituted, and the substituents are not limited. For example, one or more may be independently selected from any substituent containing a halogen atom, an O atom, a S atom, a N atom, a B atom, a Si atom, or a P atom. Examples of such substituents include optionally substituted alkyl groups, alkoxy groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, cycloalkyl groups, etc., or oxo, aminocarbonyl, halogen atoms, etc. An amino acid according to one embodiment may be a compound having a carboxy group and an amino group in the same molecule (even in this case, imino acids such as L-proline and hydroxyproline are also included in the amino acid).

[0028] As used herein, "alkyl" refers to a monovalent group derived from an aliphatic hydrocarbon by removing any one hydrogen atom, and does not contain heteroatoms (atoms other than carbon and hydrogen atoms) or unsaturated carbon-carbon bonds in the skeleton, but has a subset of hydrocarbyl or hydrocarbon group structures containing hydrogen and carbon atoms. Alkyl includes not only linear but also branched chain alkyls. Alkyl preferably has 1 to 20 carbon atoms (C １ -C ２０ Also referred to as "C" below. ｐ -C ｑ " means that the number of carbon atoms is p to q), and preferably C １ -C １０ Alkyl, more preferably C １ -C ６ Specific examples of the alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, isobutyl (also referred to as 2-methylpropyl), n-pentyl, s-pentyl (also referred to as 1-methylbutyl), t-pentyl (also referred to as 1,1-dimethylpropyl), neopentyl (also referred to as 2,2-dimethylpropyl), isopentyl (also referred to as 3-methylbutyl), 3-pentyl (also referred to as 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.

[0029] As used herein, "alkynyl" refers to a monovalent group having at least one triple bond (two adjacent SP carbon atoms). Alkynyl includes not only straight chain but also branched chain. C ２ -C １０ Alkynyl, more preferably C ２ -C ６Specific examples include alkynyl, ethynyl, 1-propynyl, propargyl, 3-butynyl, pentynyl, 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.

[0030] As used herein, "alkenyl" refers to a monovalent group having at least one double bond (two adjacent SP2 carbon atoms). Depending on the configuration of the double bond and substituents (if any), the geometry of the double bond can be entgegen (E) or zusammen (Z), cis or trans. Alkenyl includes not only straight chain but also branched chain. C is preferred as alkenyl. ２ -C １０ alkenyl, more preferably C ２ -C ６ Specific examples include vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl (including cis and trans), 3-butenyl, pentenyl, 3-methyl-2-butenyl, and hexenyl.

[0031] As used herein, the term "aryl" refers to a monovalent aromatic hydrocarbon ring or aromatic hydrocarbon ring group. Aryl is preferably C ６ -C １０ Specific examples of the aryl include phenyl and naphthyl (for example, 1-naphthyl and 2-naphthyl).

[0032] As used herein, the term "heteroaryl" refers to an aromatic cyclic monovalent group or aromatic heterocyclic group containing 1 to 5 heteroatoms in addition to carbon atoms. The ring may be a monocyclic ring or a condensed ring with another ring, and may be partially saturated. The number of atoms constituting the heteroaryl ring is preferably 5 to 10 (also referred to as a 5- to 10-membered heteroaryl), and more preferably 5 to 7 (also referred to as a 5- to 7-membered heteroaryl). Specific examples of heteroaryl include furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, azaindolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl, pyrazolopyridyl, imidazopyridyl, triazolopyridyl, pyrrolopyrazinyl, and furopyridyl.

[0033] As used herein, "aralkyl" or "arylalkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with an "aryl" as defined above. ７ -C １４ Aralkyl is preferred, C ７ -C １０ Aralkyl is more preferred. Specific examples of aralkyl include benzyl, phenethyl, and 3-phenylpropyl.

[0034] As used herein, the term "heteroaralkyl" refers to a group in which at least one hydrogen atom of an "alkyl" as defined above is substituted with a "heteroaryl" as defined above. The heteroaralkyl includes 5- to 10-membered heteroaryl C １ -C ６ Alkyl is preferred, and 5- to 10-membered heteroaryl C １ -C２ Specific examples of heteroaralkyl include 3-thienylmethyl, 4-thiazolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl, 2-(4-pyridyl)ethyl, 2-(6-quinolyl)ethyl, 2-(7-quinolyl)ethyl, 2-(6-indolyl)ethyl, 2-(5-indolyl)ethyl, and 2-(5-benzofuranyl)ethyl.

[0035] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated cyclic monovalent aliphatic hydrocarbon group, including monocyclic, bicyclic, and spirocyclic rings. ３ -C ８ Specific examples include cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, and spiro[3.3]heptyl.

[0036] In the present specification, "amino" means, in a narrow sense, -NH ２ and broadly, -NRR', where R and R' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, or R and R' together with the nitrogen atom to which they are attached form a ring. ２ , Mono C １ -C ６ Alkylamino, DiC １ -C ６ Examples thereof include alkylamino and 4- to 8-membered cyclic amino.

[0037] As used herein, "monoalkylamino" refers to a group in which R is hydrogen and R' is an "alkyl" as defined above, among the "amino" groups defined above. As the monoalkylamino group, a monoC １ -C ６Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0038] As used herein, "dialkylamino" refers to a group in which R and R' are independently "alkyl" as defined above, among the "amino" groups defined above. As dialkylamino, diC １ -C ６ Specific examples of dialkylamino include dimethylamino and diethylamino.

[0039] As used herein, "alkylsulfonylamino" refers to a group in which a sulfonyl group is bonded to the "amino" defined above. １ -C ６ Alkyl sulfonyl amino, bis(C １ -C ６ Specific examples of the aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, etc.

[0040] As used herein, "aminocarbonyl" refers to a carbonyl group to which the above-defined "amino" is bonded. The aminocarbonyl is preferably -CONH ２ , Mono (C １ -C ６ alkyl)aminocarbonyl, di(C １ -C ６ Specific examples of aminocarbonyl include -CONH ２, dimethylaminocarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, 1-piperazinylcarbonyl, 4-morpholinylcarbonyl, 3-oxazolidinylcarbonyl, 1,1-dioxidethiomorpholinyl-4-ylcarbonyl, 3-oxa-8-azabicyclo[3.2.1]octan-8-ylcarbonyl, and the like.

[0041] Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0042] Substituents derived from O atoms include hydroxy (-OH), oxy (-OR), carbonyl (-C(=O)-R), carboxy (-CO ２ H), oxycarbonyl (-C(=O)-OR), carbonyloxy (-O-C(=O)-R), thiocarbonyl (-C(=O)-SR), carbonylthio group (-S-C(=O)-R), aminocarbonyl (-C(=O)-NHR), carbonylamino (-NH-C(=O)-R), oxycarbonylamino (-NH-C(=O)-OR), sulfonylamino (-NH-SO ２ -R), aminosulfonyl (-SO ２ -NHR), sulfamoylamino (-NH-SO ２ -NHR), thiocarboxy (-C(=O)-SH), carboxylcarbonyl (-C(=O)-CO ２ H).

[0043] Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like.

[0044] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0045] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0046] Examples of carbonyloxy (—O—C(═O)—R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0047] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0048] Examples of carbonylthio (-S-C(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0049] Examples of aminocarbonyl (-C(=O)-NHR) include alkylaminocarbonyl, cycloalkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, aralkylaminocarbonyl, etc. In addition to these, compounds in which the H atom bonded to the N atom in -C(=O)-NHR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0050] Examples of carbonylamino (-NH-C(=O)-R) include alkylcarbonylamino, cycloalkylcarbonylamino, alkenylcarbonylamino, alkynylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aralkylcarbonylamino, etc. In addition to these, compounds in which the H atom bonded to the N atom in -NH-C(=O)-R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl are also included.

[0051] Examples of oxycarbonylamino (-NH-C(=O)-OR) include alkoxycarbonylamino, cycloalkoxycarbonylamino, alkenyloxycarbonylamino, alkynyloxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, aralkyloxycarbonylamino, etc. In addition to these, examples include compounds in which the H atom bonded to the N atom in -NH-C(=O)-OR is further substituted with an alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0052] Sulfonylamino (-NH-SO ２ Examples of —R) include alkylsulfonylamino, cycloalkylsulfonylamino, alkenylsulfonylamino, alkynylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, aralkylsulfonylamino, etc. In addition to these, —NH—SO ２ Examples include compounds in which the H atom bonded to the N atom in —R is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0053] Aminosulfonyl (-SO ２ Examples of —NHR) include alkylaminosulfonyl, cycloalkylaminosulfonyl, alkenylaminosulfonyl, alkynylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, and the like. ２Examples include compounds in which the H atom bonded to the N atom in —NHR is further substituted with alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or aralkyl.

[0054] Sulfamoylamino (-NH-SO ２ Examples of —NHR) include alkylsulfamoylamino, cycloalkylsulfamoylamino, alkenylsulfamoylamino, alkynylsulfamoylamino, arylsulfamoylamino, heteroarylsulfamoylamino, and aralkylsulfamoylamino. ２ The two H atoms bonded to the N atom in —NHR may be substituted with substituents independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and these two substituents may form a ring.

[0055] Substituents derived from S atoms include thiol (-SH), thio (-S-R), sulfinyl (-S(=O)-R), sulfonyl (-S(O) ２ -R), sulfo (-SO ３ H), pentafluorosulfanyl (-SF ５ ) etc.

[0056] Examples of thio (-S-R) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0057] Examples of sulfinyl (-S(=O)-R) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0058] Sulfonyl (-S(O) ２ Examples of —R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0059] As a substituent derived from the N atom, azide (-N ３ , also called "azido group"), cyano (-CN), primary amino (-NH ２ ), secondary amino (—NH—R), tertiary amino (—NR(R′)), amidino (—C(═NH)—NH ２ ), substituted amidino (—C(═NR)—NR′R″), guanidino (—NH—C(═NH)—NH ２ ), substituted guanidino (—NR—C(═NR′″)—NR′R″), aminocarbonylamino (—NR—CO—NR′R″), and the like.

[0060] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0061] Examples of tertiary amino (—NR(R′)) include an amino group having any two substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., such as alkyl(aralkyl)amino, and these two substituents may form a ring.

[0062] Examples of substituted amidino (-C(=NR)-NR'R'') include groups 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, such as alkyl(aralkyl)(aryl)amidino.

[0063] Examples of substituted guanidino (-NR-C(=NR'")-NR'R") include groups in which R, R', R", and R'" are each independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these groups form a ring.

[0064] Examples of aminocarbonylamino (—NR—CO—NR′R″) include groups in which R, R′, and R″ are each independently selected from a hydrogen atom, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, and aralkyl, and groups in which these groups form a ring.

[0065] Examples of the substituent derived from the B atom include boryl (-BR(R')) and dioxyboryl (-B(OR)(OR')). These two substituents R and R' may be groups independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, etc., or may be a group in which these groups form a ring. Specific examples include cyclic boryl groups, and more specific examples include pinacolatoboryl groups, neopentanediolateboryl groups, and catecholateboryl groups.

[0066] The main chain amino group of the amino acid is unsubstituted (-NH ２ ) or may be substituted with R (i.e., represented by —NHR. In the formula, R represents, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, a cycloalkyl group, or the like, which may have a substituent, and the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring, as in proline).

[0067] The peptide of this embodiment may have a cyclic portion, and preferably has a cyclic portion. In other words, the peptide of this embodiment may be a cyclic peptide, and preferably is a cyclic peptide. As used herein, a "cyclic peptide" is a peptide having a cyclic structure (i.e., a cyclic portion) composed of four or more amino acid residues. The cyclization of the cyclic peptide may be any form, such as cyclization via a carbon-nitrogen bond such as an amide bond, cyclization via a carbon-oxygen bond such as an ester bond or an ether bond, cyclization via a carbon-sulfur bond such as a thioether bond, cyclization via a carbon-carbon bond, or cyclization via a heterocyclic ring structure. Among these, cyclization via a covalent bond such as an amide bond, a carbon-sulfur bond, or a carbon-carbon bond is preferred. Cyclization via an amide bond is more preferred, and the position of the carboxyl group or amino group used for cyclization may be on either the main chain or the side chain. Most preferred is cyclization via an amide bond between a carboxyl group in the side chain and an amino group in the main chain at the N-terminus.

[0068] "Cyclization" of a peptide refers to the formation of a cyclic portion containing four or more amino acid residues. A linear peptide can be converted into a cyclic peptide by carrying out an intramolecular bond formation reaction using a method such as that described in "Comprehensive Organic Transformations, A Guide to Functional Group Preparations, 3rd Edition" (by R.C. Larock) or "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th Edition" (by M.B. Smith and J. March). After the bond formation reaction, a functional group transformation reaction can also be carried out. Examples of the bond at the cyclization site of a cyclic peptide include a C(O)-N bond formed between a carboxylic acid and an amine, a C-O-C bond mediated by an oxygen atom, a C(O)-O bond, a C(S)-O bond, a C(O)-S bond mediated by a sulfur atom, a C(S)-S bond, a C-S-C bond, a C-S-C bond, a C-S-C bond, a C-S-C bond, a C-N-C bond, a C=N-C bond, an N-C(O)-N bond, an N-C(S)-N bond, and a C(S)-N bond mediated by a nitrogen atom. Further examples include C-C bonds formed by transition metal-catalyzed coupling reactions such as the Suzuki reaction, the Heck reaction, and the Sonogashira reaction. Examples of functional group conversion reactions that can be carried out after the bond formation reaction include oxidation reactions and reduction reactions. Specifically, examples include reactions in which a sulfur atom is oxidized to form a sulfoxide group or a sulfone group. Another example is a reduction reaction in which a triple or double bond among carbon-carbon bonds is reduced to form a double or single bond. Two amino acids may be linked at the main chain of the amino acid to form a closed ring structure by a peptide bond, or a covalent bond between the two amino acids may be formed by bonding the side chains of the two amino acids together, or between the side chain and the main chain, etc.

[0069] As used herein, the term "heterocycle" refers to a non-aromatic heterocycle containing preferably 1 to 5, more preferably 1 to 3, heteroatoms among the atoms constituting the ring. The heterocycle may have a double and / or triple bond in the ring, and a carbon atom in the ring may be oxidized to form a carbonyl, and may be a monocyclic, fused, or spirocyclic ring. The number of atoms constituting the heterocycle ring is preferably 3 to 12 (3- to 12-membered heterocycle), more preferably 4 to 10 (4- to 10-membered heterocycle). Specific examples of the heterocyclic ring include an azetidine ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine ring, a pyrrolidine ring, a 4-oxopyrrolidine ring, a piperidine ring, a 4-oxopiperidine ring, a piperazine ring, a pyrazolidine ring, an imidazolidine ring, an oxazolidine ring, an isoxazolidine ring, a thiazolidine ring, an isothiazolidine ring, a thiadiazolidine ring, and an oxazolidone ring. , a dioxolane ring, a dioxane ring, a thietane ring, an octahydroindole ring, a 6,7-dihydro-pyrrolo[1,2-a]imidazole ring, an azocane ring, a 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine ring, an azepane ring, a dioxepane ring, a 5,9-dioxaspiro[3.5]nonane ring, or a ring in which one or more single bonds in these saturated heterocycles are replaced with double bonds or triple bonds.

[0070] In this embodiment, the number of amino acid residues constituting the cyclic portion of the cyclic peptide is not particularly limited, and may be, for example, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, or 11 or more, and may be 15 or less, 14 or less, 13 or less, 12 or less, or 11 or less. The number of amino acid residues constituting the cyclic portion of the cyclic peptide in this embodiment is not particularly limited, and may be, for example, 5 or more and 15 or less, 6 or more and 15 or less, 7 or more and 15 or less, 8 or more and 15 or less, 9 or more and 15 or less, 10 or more and 14 or less, 11 or more and 13 or less, 11 or more and 12 or less, or 11. The number of amino acid residues constituting the cyclic portion of the cyclic peptide in this embodiment is not particularly limited, and may be, for example, 5 or more and 15 or less, preferably 10 or more and 14 or less, more preferably 11 or more and 13 or less, and most preferably 11.

[0071] In this embodiment, the cyclic portion of the cyclic peptide is not particularly limited, and may be, for example, a 28-55, 28-49, 31-46, 34-43, 34-40, 34-37, or 34-membered ring. In this embodiment, the cyclic portion of the cyclic peptide is not particularly limited, and may be, for example, a 28-55-membered ring, preferably a 31-46-membered ring, more preferably a 34-37-membered ring, and most preferably a 34-membered ring.

[0072] As used herein, the term "N-substituted amino acid" refers to an amino acid in which the amino group contained therein is substituted, i.e., -NHR (wherein R represents an alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl group which may have a substituent, and one or two non-adjacent methylene groups in these groups are replaced with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO ２ -), or, as in proline, the carbon chain bonded to the N atom and the carbon atom at the α-position may form a ring.

[0073] The N-substituted amino acid in this embodiment is not particularly limited, but may be an N-alkylamino acid, which may form a ring together with the carbon atom bonded to the nitrogen atom constituting the main chain and the nitrogen atom. １ -C ６ An "N-substituted amino acid" is an alkyl amino acid, which may form a ring together with the carbon atom bonded to the nitrogen atom constituting the main chain and the nitrogen atom. The "N-substituted amino acid" in this embodiment is more preferably an N-ethyl amino acid or an N-methyl amino acid, and most preferably an N-methyl amino acid.

[0074] The number of N-substituted amino acid residues contained in the peptide of this embodiment is not particularly limited, and may be, for example, 1 or more, 2 or more, 3 or more, 4 or more, 5 or more, or 6 or more. The number of N-substituted amino acid residues contained in the peptide of this embodiment is not particularly limited, and is, for example, 1 or more, preferably 3 or more, more preferably 4 or more, and most preferably 5 or more.

[0075] As used herein, an "N-unsubstituted amino acid" refers to an amino acid in which the amino group contained therein is not substituted, i.e., -NH ２ As used herein, the "N-unsubstituted amino acid" is preferably an N-unsubstituted amino acid in which the amino group contained in the "amino acid main chain" is not substituted.

[0076] The number of N-unsubstituted amino acid residues contained in the peptide of this embodiment is not particularly limited, and may be, for example, 1 or more, 2 or more, or 3 or more. The number of N-unsubstituted amino acid residues contained in the peptide of this embodiment is not particularly limited, and may be, for example, 1 or more, preferably 2 or more, more preferably 3 or more, and most preferably 3 or more.

[0077] As used herein, the term "main chain of an amino acid" refers to the atomic group (also referred to as a "partial structure") that connects an amino group and a carboxy group with the minimum number of atoms, and is generally common to all amino acids. In the case of α-amino acids, it refers to the chain portion composed of an amino group, an α-carbon, and a carboxy group; in the case of β-amino acids, it refers to the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxy group; and in the case of γ-amino acids, it refers to the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group. The terms "α-carbon," "β-carbon," and "γ-carbon" refer to the carbon atoms located first, second, and third, respectively, counting from the carboxy group. The term "α-amino acid" means that an amino group is bonded to the α-carbon, and similar expressions are understood similarly. Furthermore, the term "α-amino acid backbone" refers to a chain portion composed of an amino group, an α-carbon, and a carboxy group, the term "β-amino acid backbone" refers to a chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxy group, and the term "γ-amino acid backbone" refers to a chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxy group. In this specification, an amino acid having a "β-amino acid backbone" as an entire or partial structure may be referred to as an "amino acid having a β-amino acid backbone." For example, L-aspartic acid has a chain portion (β-amino acid backbone) composed of an amino group, a β-carbon, an α-carbon, and a carboxy group, and therefore corresponds to an "amino acid having a β-amino acid backbone."

[0078] As used herein, the term "side chain of an amino acid" refers to, in the case of an α-amino acid, an atomic group other than the amino group and the carboxyl group that is bonded to the carbon (α-carbon) to which the amino group and the carboxyl group are bonded. For example, the methyl group of Ala is the side chain of an amino acid. In the case of a β-amino acid, an atomic group bonded to the α-carbon and / or the β-carbon, other than the amino group bonded to the β-carbon and the carboxy group bonded to the α-carbon, can serve as the side chain of an amino acid. In the case of a γ-amino acid, an atomic group bonded to the α-carbon, the β-carbon, and / or the γ-carbon, other than the amino group bonded to the γ-carbon and the carboxy group bonded to the α-carbon, can serve as the side chain of an amino acid.

[0079] The peptide in this embodiment may contain at least one β-amino acid backbone, and preferably contains at least one β-amino acid backbone.

[0080] When the peptide of this embodiment has a cyclic portion, the peptide of this embodiment may contain at least one β-amino acid backbone in the cyclic portion, and preferably contains at least one β-amino acid backbone in the cyclic portion.

[0081] As used herein, the term "substituted hydroxyphenyl group" refers to a group in which at least one hydrogen atom in the aromatic ring of a hydroxyphenyl group is replaced with a substituent. The substituent is not particularly limited, and may be freely selected from, in addition to a hydrogen atom, for example, a halogen, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, a heteroaryl group, an aralkyl group, or a cycloalkyl group, and one or two non-adjacent methylene groups in these groups may be replaced with an oxygen atom, a carbonyl group (-CO-), or a sulfonyl group (-SO ２ -). Each of these may be substituted with a substituent, and the substituents are not limited, and may be independently selected from any substituents containing a halogen atom, an O atom, an S atom, an N atom, a B atom, a Si atom, or a P atom. Examples of substituted hydroxyphenyl groups include optionally substituted alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, and cycloalkyl groups. Preferred examples include halogen atoms, and fluorine is particularly preferred. While not intended to be limiting, an example of a substituted hydroxyphenyl group is a 3-fluoro-4-hydroxyphenyl group. Note that, in this specification, the hydrogen atoms of the aromatic ring do not include the H of the hydroxy group (—OH) in the hydroxyphenyl group. For example, a methoxyphenyl group is not included in either a "substituted hydroxyphenyl group" or an "unsubstituted hydroxyphenyl group" in this specification.

[0082] In this specification, the term "unsubstituted hydroxyphenyl group" refers to a hydroxyphenyl group that has no substituent. In addition, substituted hydroxyphenyl groups and unsubstituted hydroxyphenyl groups may be collectively referred to as "substituted or unsubstituted hydroxyphenyl groups."

[0083] In this specification, "having no substituted or unsubstituted XX group" means having neither a substituted XX group nor an unsubstituted XX group.

[0084] The peptide in this embodiment may not have an indolyl group, may not have a substituted or unsubstituted hydroxyphenyl group, or may not have an indolyl group and a substituted or unsubstituted hydroxyphenyl group. The peptide in this embodiment preferably has no indolyl group or no substituted or unsubstituted hydroxyphenyl group, and more preferably has no indolyl group and a substituted or unsubstituted hydroxyphenyl group.

[0085] As used herein, the "number of aromatic rings" (also referred to as "Aromatic Ring Count" (ARC)) refers to the number of aromatic rings contained in the peptide portion other than the nucleic acid linking portion of a cyclic peptide, the cyclic portion, or the side chain of the cyclic portion; for example, a phenol group is counted as one, a bicyclic fused ring such as an indole skeleton is counted as two, and a tricyclic fused ring such as anthracene is counted as three.

[0086] The number of aromatic rings contained in the peptide of this embodiment is not particularly limited, and may be, for example, 0 to 3 or 1 to 3. The number of aromatic rings contained in the peptide of this embodiment is not particularly limited, and may be, for example, 0 to 3, preferably 0 to 3, more preferably 1 to 3, and most preferably 1 to 3. "The number of aromatic rings contained in the peptide is 0" means that the peptide has no aromatic rings, and "The number of aromatic rings contained in the peptide is 0 to 3" means that the peptide has no aromatic rings or 1, 2, or 3 aromatic rings.

[0087] As used herein, "ClogP" refers to a computer-calculated partition coefficient. ClogP can be determined in accordance with the principles described in Daylight Version 4.9 from Daylight Chemical Information Systems, Inc. (https: / / www.daylight.com / dayhtml / doc / clogp / ). One example of a method for calculating ClogP is using Daylight Version 4.95 from Daylight Chemical Information Systems, Inc. (release date: August 1, 2011, ClogP algorithm version 5.4, database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html).

[0088] In this embodiment, the ClogP of the peptide is not particularly limited, and may be, for example, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, or 9 or more, and may be, for example, 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, or 20 or less. In this embodiment, the ClogP of the peptide is not particularly limited, and may be, for example, 4 or more and 25 or less, 5 or more and 24 or less, 6 or more and 23 or less, 7 or more and 22 or less, 8 or more and 21 or less, or 9 or more and 20 or less. In this embodiment, the ClogP of the peptide is not particularly limited, and may be, for example, 4 or more and 25 or less, preferably 6 or more and 23 or less, more preferably 8 or more and 21 or less, and most preferably 9 or more and 20 or less.

[0089] In this embodiment, the ClogP of the peptide is not particularly limited, but may be, for example, equal to or greater than the ClogP value of the peptide (CP02) shown below.

[0090] As used herein, "ClogP / number of amino acid residues" refers to a value calculated by dividing the ClogP of a peptide by the number of amino acid residues contained in the peptide. For example, if the ClogP of a peptide is 14.0 and the number of amino acid residues contained in the peptide is 7, the ClogP / number of amino acid residues of the peptide is calculated to be 2.0.

[0091] In this embodiment, the Clog P / number of amino acid residues of the peptide is not particularly limited, but may be, for example, 1.0 or more or 1.1 or more, or 1.8 or less, 1.7 or less, 1.6 or less, or 1.5 or less. In this embodiment, the Clog P / number of amino acid residues of the peptide is not particularly limited, but may be, for example, 1.0 to 1.8 or 1.0 to 1.7 or 1.1 to 1.6 or 1.1 to 1.5. The Clog P / number of amino acid residues of the peptide is not particularly limited, but may be, for example, 1.0 to 1.8 or preferably 1.0 to 1.7, more preferably 1.1 to 1.6, and most preferably 1.1 to 1.5.

[0092] In this embodiment, the peptide is not particularly limited, but may exclude, for example, peptides represented by the following formulas ECP1 to ECP5 (corresponding to SEQ ID NOs: 5 to 9, respectively).

[0093] In this embodiment, the peptide may be in an amorphous form. Also, in this embodiment, the peptide may be in a crystalline form.

[0094] [Surfactant Having a Sugar Fatty Acid Ester Structure] In this embodiment, the surfactant having a sugar fatty acid ester structure has a sugar moiety as the hydrophilic portion and a fatty acid moiety as the hydrophobic portion, with the fatty acid moiety being ester-bonded to the hydroxyl group of the sugar moiety. The surfactant in this embodiment has one or more fatty acid moieties per sugar moiety. When the surfactant has two or more fatty acid moieties, the fatty acid moieties may be the same or different fatty acids. A sugar fatty acid ester having one fatty acid moiety per sugar moiety is called a monoester, a sugar fatty acid ester having two fatty acid moieties is called a diester, and a sugar fatty acid ester having three fatty acid moieties is called an ester. Furthermore, particularly when a sugar fatty acid ester contains multiple different fatty acid structures, the sugar fatty acid ester is also called a mixed sugar fatty acid ester. In certain embodiments, the surfactant may be a monoester, a diester, a triester, or a mixture thereof. When the surfactant is a mixture of multiple sugar fatty acid esters, the combination (also referred to herein as the "ester composition") preferably includes at least one selected from the group consisting of a monoester, a diester, and a triester, more preferably at least one selected from the group consisting of a monoester and a diester, and most preferably includes a monoester and a diester. The proportion of monoester in the ester composition may be, for example, 80% by weight or more, preferably 90% by weight or more, more preferably 95% by weight or more, and most preferably 98% by weight or more, based on the total weight of the surfactant. In a preferred aspect of this embodiment, the surfactant having a sugar fatty acid ester structure is a nonionic surfactant.

[0095] In one aspect of this embodiment, the sugar moiety includes monosaccharides such as erythrose, threose, xylose, arabinose, D-glucose, D-thioglucose, D-galactose, and D-idose, and disaccharides such as sucrose (cane sugar), lactulose, lactose, maltose, isomaltose, trehalose, and cellobiose. The sugar moiety is preferably a disaccharide, and more preferably sucrose. In one aspect of this embodiment, the surfactant having a sugar fatty acid ester structure is a sucrose fatty acid ester.

[0096] In one aspect of this embodiment, the fatty acid moiety is not limited as long as it is a hydrocarbon having a carboxy group at its terminal. The hydrocarbon may be a saturated hydrocarbon (alkane) or an unsaturated hydrocarbon (alkene, alkyne). The number of carbon atoms (including carboxy carbons) of the fatty acid may be 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, 10 or more, 11 or more, 12 or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, or 18 or more. The number of carbon atoms of the fatty acid may be 30 or less, 29 or less, 28 or less, 27 or less, 26 or less, 25 or less, 24 or less, 23 or less, 22 or less, 21 or less, or 20 or less. The number of carbon atoms of the fatty acid moiety is, for example, 13 to 30, preferably 14 to 24, more preferably 15 to 20, and most preferably 16 to 18. Generally, fatty acids with fewer than 6 carbon atoms are called "short-chain fatty acids," fatty acids with 6 to 12 carbon atoms are called "medium-chain fatty acids," and fatty acids with 13 or more carbon atoms are called "long-chain fatty acids." Examples of fatty acids include butanoic acid (butyric acid), pentanoic acid (valeric acid), hexanoic acid (caproic acid) (carbon number 6), heptanoic acid, octanoic acid (caprylic acid) (carbon number 8), nonanoic acid, decanoic acid (capric acid) (carbon number 10), dodecanoic acid (lauric acid) (carbon number 12), tetradecanoic acid (myristic acid) (carbon number 14), pentadecanoic acid, hexadecanoic acid (palmitic acid) (carbon number 16), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid) (carbon number 18), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, cis,cis-9,12-octadecadienoic acid (linoleic acid), eicosanoic acid (arachidic acid), and docosanoic acid (behenic acid).

[0097] Among these, the fatty acid moiety of the surfactant is at least one selected from the group consisting of tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, cis,cis-9,12-octadecadienoic acid (linoleic acid), eicosanoic acid (arachidic acid), and docosanoic acid (behenic acid), and preferably pentadecanoic acid, hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, cis,cis-9,12-octadecadienoic acid (linoleic acid), eicosanoic acid (arachidic acid), and docosanoic acid (behenic acid). The acid is at least one selected from the group consisting of decenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, and cis,cis-9,12-octadecadienoic acid (linoleic acid), more preferably at least one selected from the group consisting of hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, and octadecanoic acid (stearic acid), and most preferably hexadecanoic acid (palmitic acid) and octadecanoic acid (stearic acid).

[0098] When the surfactant is a mixture of multiple types of sugar fatty acid esters, the combination of fatty acids (also referred to as "fatty acid composition" in this specification) includes at least one selected from the group consisting of tetradecanoic acid (myristic acid), pentadecanoic acid, hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, cis,cis-9,12-octadecadienoic acid (linoleic acid), eicosanoic acid (arachidic acid), and docosanoic acid (behenic acid), and preferably pentadecanoic acid , hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, octadecanoic acid (stearic acid), cis-9-octadecenoic acid (oleic acid), 11-octadecenoic acid, and cis,cis-9,12-octadecadienoic acid (linoleic acid), more preferably at least one selected from the group consisting of hexadecanoic acid (palmitic acid), 9-hexadecenoic acid (palmitoleic acid), heptadecanoic acid, and octadecanoic acid (stearic acid), and most preferably hexadecanoic acid (palmitic acid) and octadecanoic acid (stearic acid).

[0099] When the surfactant is a mixture of multiple types of sugar fatty acid esters having different numbers of carbon atoms in the fatty acid moieties, the proportion of stearic acid in the fatty acid composition may be, for example, 10% by weight or more, preferably 20% by weight or more, more preferably 30% by weight or more, and most preferably 50% by weight or more, relative to the total weight of the surfactant.

[0100] In certain embodiments, the proportion of stearic acid in the fatty acid composition may be 10% by weight or more, preferably 20% by weight or more, more preferably 30% by weight or more, and most preferably 50% by weight.

[0101] In one aspect of this embodiment, the surfactant having a sugar fatty acid ester structure has an HLB value of 1 to 20. In one aspect of this embodiment, the HLB value of the surfactant having a sugar fatty acid ester structure is 1 to 19, 1 to 18, 1 to 17, 1 to 16, 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 3 to 19, 3 to 18, 3 to 17, 3 to 16, 3 to 15, 3 to 14, 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 5 to 19, 5 to 18, 5 to 17, 5 to 16, 5 to 15, 5 to 14, 5 to 13, 5 to 12, 5 to 11, 5 to 10, 5 to 9 , 5 to 8, 5 to 7, 5 to 6, 7 to 19, 7 to 18, 7 to 17, 7 to 16, 7 to 15, 7 to 14, 7 to 13, 7 to 12, 7 to 11, 7 to 10, 7 to 9, 7 to 8, 9 to 19, 9 to 18, 9 to 17, 9 to 16, 9 to 15, 9 to 14, 9 to 13, 9 to 12, 9 to 11, 9 to 10, 11 to 19, 11 to 18, 11 to 17, 11 to 16, 11 to 15, 11 to 14, 11 to 13, 11 to 12, 13 to 19, 13 to 18, 13 to 17, 13 to 16, 13 to 15, 13 to 14, 15 to 19, 15 to 18, 15 to 17, 15 to 16, 17 to 19, or 17 to 18. In one aspect of this embodiment, the HLB value of the surfactant having a sugar fatty acid ester structure is, for example, 1 or more and 20 or less, preferably 5 or more and 20 or less, more preferably 10 or more and 20 or less, and most preferably 15 or more and 20 or less. The HLB value can be calculated by methods well known to those skilled in the art, such as the Griffin method, the Kawakami method, the Davies method, and the Oda method. The HLB value may be a numerical value listed in a catalog or publication.

[0102] The solid dispersion according to this embodiment may contain, in addition to the surfactant having a sugar fatty acid ester structure, a surfactant such as a cationic surfactant, an anionic surfactant, an amphoteric surfactant, or a nonionic surfactant.

[0103] The anionic surfactant in this embodiment is not particularly limited, but examples thereof include fatty acid salts, rosinate salts, alkyl sulfates, alkyl polyoxyethylene sulfates, alkyl naphthalene sulfates, lignin sulfates, and alkyl phosphates, which may be used alone or in combination. The anionic surfactant in this embodiment may be, for example, fatty acid salts, rosinate salts, alkyl sulfates, alkyl polyoxyethylene sulfates, alkyl naphthalene sulfates, lignin sulfates, or alkyl phosphates, with alkyl sulfates being preferred, lauryl sulfate being more preferred, and sodium lauryl sulfate being most preferred.

[0104] In one aspect of this embodiment, the amphoteric surfactant may be any surfactant having both a positively charged functional group and a negatively charged functional group. The amphoteric surfactant in this embodiment is not particularly limited, but examples include acylcarnitine, N-alkyl β-aminopropionic acid, N-alkyl sulfobetaine, and N-alkylhydroxysulfobetaine, which may be used alone or in combination of two or more. The amphoteric surfactant in this embodiment is preferably acylcarnitine, N-alkyl β-aminopropionic acid, N-alkyl sulfobetaine, or N-alkylhydroxysulfobetaine, and more preferably acylcarnitine. As the acylcarnitine, lauroylcarnitine or carnitine palmitate is preferred, lauroylcarnitine is more preferred, and lauroyl-L-carnitine is most preferred.

[0105] The nonionic surfactant in the present embodiment is not particularly limited, and examples thereof include alkyl polyoxyethylene ethers, alkylaryl polyoxyethylene ethers, polyoxyethylene fatty acid esters, polyoxyethylene glycerin fatty acid esters, sorbitan fatty acid esters, polyglycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, and poloxamer (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), polyoxyethylene hydrogenated castor oil, and D-α-tocopherol polyethylene glycol 1000 succinate, and these may be used alone or in combination of two or more.

[0106] [Polymer] In the present embodiment, the solid dispersion contains a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

[0107] In one aspect of this embodiment, the solid dispersion contains (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, and (3) the polymer. The polymer is present in a dispersed state throughout the solid dispersion, which differs from an aspect in which the polymer is unevenly distributed on the surface, such as in a coating. Such a solid dispersion can be produced by mixing the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer (the three components shown as (1) to (3)) with a solvent, if necessary, and then removing the solvent. In one aspect of this embodiment, for example, the solid dispersion can be produced by mixing the three components, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer, together with a solvent, if necessary, and then removing the solvent from the resulting composition.

[0108] When the solid dispersion according to this embodiment contains the above-mentioned polymer, the solubility of the peptide contained in the solid dispersion can be efficiently increased.

[0109] In one aspect of this embodiment, the peptide has the formula: In the case of a peptide (CP02) represented by the formula (I), the solubility of CP02 can be efficiently increased by formulating it into the solid dispersion according to this embodiment.

[0110] The polymer according to this embodiment is a polymer containing at least one monomer unit selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl esters, (meth)acrylic acid alkylamino alkyl esters, and (meth)acrylic acid ammonio alkyl esters. The polymer may be a polymer formed by polymerizing a single monomer, such as poly(meth)acrylic acid, poly(meth)acrylic acid alkyl esters, poly(meth)acrylic acid alkylamino alkyl esters, or poly(meth)acrylic acid ammonio alkyl esters, or may be a copolymer containing at least one of these monomer units. When the polymer according to this embodiment is a copolymer, the polymer may be a copolymer formed from two or more monomers, or may be a copolymer formed from three or more, or four or more, monomers. The copolymer may also be a block copolymer or a random copolymer. Examples of block copolymers include diblock copolymers, triblock copolymers, and tetrablock copolymers. In one aspect of this embodiment, such a polymer may be a copolymer of acrylic acid and methacrylic acid, a copolymer of an alkyl (meth)acrylate ester and (meth)acrylic acid, a copolymer of multiple types of alkyl (meth)acrylate esters (for example, a copolymer of alkyl acrylate esters having different alkyl groups, or a copolymer of an alkyl acrylate ester and an alkyl methacrylate ester), a copolymer of an alkyl (meth)acrylate ester and an alkylamino (meth)acrylate ester, or a copolymer of an alkyl (meth)acrylate ester and an ammonio alkyl (meth)acrylate ester. The above polymers may be used alone or in combination of two or more.The polymer according to this embodiment is preferably a methacrylic acid / ethyl acrylate copolymer, a methacrylic acid / methyl methacrylate copolymer, a copolymer of acrylic acid and methacrylic acid, a copolymer of a (meth)acrylic acid alkyl ester and (meth)acrylic acid, a copolymer of a (meth)acrylic acid alkyl ester and a (meth)acrylic acid alkylamino alkyl ester, or a copolymer of a (meth)acrylic acid alkyl ester and a (meth)acrylic acid ammonio alkyl ester. An example of the polymer according to this embodiment is aminoalkyl methacrylic acid copolymer E (manufactured by Evonik).

[0111] The polymer may contain at least one monomer unit selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl ester, (meth)acrylic acid alkylamino alkyl ester, and (meth)acrylic acid ammonio alkyl ester, and may also contain other polymerizable monomers (for example, substituted or unsubstituted styrene (for example, para-hydroxystyrene), vinyl acetate, N-substituted or unsubstituted maleimide, etc.).

[0112] The polymer according to this embodiment is preferably a copolymer of a (meth)acrylic acid alkyl ester and at least one monomer selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, and a (meth)acrylic acid alkylaminoalkyl ester.

[0113] The polymer according to this embodiment is preferably a copolymer of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid and an alkylaminoalkyl (meth)acrylate.

[0114] The polymer according to this embodiment is preferably a copolymer of an alkyl (meth)acrylate and (meth)acrylic acid.

[0115] The polymer according to this embodiment is preferably a copolymer of methyl methacrylate or ethyl acrylate and (meth)acrylic acid. The copolymer according to this embodiment may be at least one selected from the group consisting of a copolymer of methyl methacrylate and methacrylic acid and a copolymer of ethyl acrylate and methacrylic acid.

[0116] The polymer according to this embodiment is more preferably a copolymer of methyl methacrylate and methacrylic acid. Note that the copolymer of a (meth)acrylic acid alkyl ester and a (meth)acrylic acid alkyl ester differs in the type of alkyl in the alkyl ester or in the methacrylic acid and the acrylic acid.

[0117] The (meth)acrylic acid in this embodiment is not particularly limited, but is preferably methacrylic acid.

[0118] In this specification, the term "(meth)acrylic acid alkyl ester" means "acrylic acid alkyl ester and / or methacrylic acid alkyl ester." The (meth)acrylic acid ester in this embodiment is not particularly limited, but may be, for example, (meth)acrylic acid C １ -C ６ It may be an alkyl ester, preferably methyl (meth)acrylic acid ester or ethyl (meth)acrylic acid ester, more preferably methyl methacrylate or ethyl acrylate, and most preferably methyl methacrylate.

[0119] Furthermore, the term "(meth)acrylic acid alkylaminoalkyl ester" in this specification means "acrylic acid alkylaminoalkyl ester" or "methacrylic acid alkylaminoalkyl ester." The (meth)acrylic acid alkylaminoalkyl ester in this embodiment is not particularly limited, but is preferably 2-(dimethylamino)ethyl (meth)acrylate, and more preferably 2-(dimethylamino)ethyl methacrylate.

[0120] Furthermore, the term "(meth)acrylic acid ammonio alkyl ester" in this specification means "acrylic acid ammonio alkyl ester" or "methacrylic acid ammonio alkyl ester." The (meth)acrylic acid ammonio alkyl ester in this embodiment is not particularly limited, but may be, for example, trialkylammonium alkyl (meth)acrylic acid chloride (also referred to as [(meth)acryloyloxyalkyl]trialkylammonium chloride), and is preferably trimethylammonium ethyl methacrylic acid chloride (also referred to as [2-(methacryloyloxy)ethyl]trimethylammonium chloride).

[0121] In the polymer according to the present embodiment, which comprises at least one selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl esters, (meth)acrylic acid alkylaminoalkyl esters, and (meth)acrylic acid ammonioalkyl esters, the ratio of units derived from (meth)acrylic acid alkyl esters to units derived from at least one monomer selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl esters, (meth)acrylic acid alkylaminoalkyl esters, and (meth)acrylic acid ammonioalkyl esters is not particularly limited, but may be, for example, a molar ratio of 10:90 to 90:10, 20:80 to 80:20, 30:70 to 70:30, 40:60 to 60:40, or 45:55 to 55:45, and is preferably 40:60 to 60:40.

[0122] The number average molecular weight of the copolymer of the (meth)acrylic acid alkyl ester and at least one monomer selected from the group consisting of (meth)acrylic acid, (meth)acrylic acid alkyl esters, (meth)acrylic acid alkylaminoalkyl esters, and (meth)acrylic acid ammonioalkyl esters according to this embodiment is not particularly limited, and may be, for example, 10,000 g / mol to 10,000,000 g / mol, 30,000 g / mol to 3,000,000 g / mol, or 100,000 g / mol to 1,000,000 g / mol.

[0123] In addition to the above polymers, the solid dispersion according to this embodiment may contain the following additional polymers: (I) hydroxypropyl methylcellulose or a derivative thereof; (II) copovidone; (III) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; and (IV) polyvinylpyrrolidone.

[0124] In this embodiment, the additional polymer is preferably an ionic polymer, more preferably an acidic polymer.

[0125] As used herein, the term "ionic polymer" refers to a polymer that has substantially ionic functional groups and is at least about 10% ionized over at least a portion of the physiologically relevant pH range of 1 to 8. Examples of ionic polymers include acidic polymers and basic polymers. Ionic polymers are generally classified into acidic polymers and basic polymers in the pH range in which they are ionized, and acidic polymers (or enteric polymers) are soluble in neutral or alkaline solutions.

[0126] In this embodiment, examples of the acidic polymer include cellulose acetate phthalate, cellulose acetate trimellitate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethylcellulose ethyl phthalate, hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methyl acetate maleate, hydroxypropyl methyl trimellitate, carboxymethyl ethyl cellulose, polyvinyl butyrate phthalate, and polyvinyl alcohol acetate phthalate.

[0127] In this embodiment, an example of the basic polymer is polyvinyl acetal diethylamino acetate.

[0128] In a preferred aspect of this embodiment, the additional polymer may be, for example, hydroxypropyl methylcellulose or a derivative thereof, preferably hydroxypropyl methylcellulose or an ester thereof, more preferably at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate, and most preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0129] Hydroxypropyl methylcellulose is also known as hypromellose. In this specification, the term "hydroxypropyl methylcellulose derivative" refers to a polymer obtained by reacting (modifying) the hydroxyl groups of hydroxypropyl methylcellulose, and examples thereof include esters, ethers, carbamates, and carbonates of hydroxypropyl methylcellulose. In the hydroxypropyl methylcellulose derivative according to this embodiment, the proportion of modified hydroxyl groups of hydroxypropyl methylcellulose is not particularly limited, but may be, for example, 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, or 80% or more.

[0130] The hydroxypropyl methylcellulose or derivative thereof in this embodiment is not particularly limited, but is preferably hydroxypropyl methylcellulose or an ester thereof, more preferably at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate, and most preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0131] Copovidone (also known as copolyvidone) is a copolymer of 1-vinyl-2-pyrrolidone and vinyl acetate in a content ratio of about 3:2 by weight.

[0132] The polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is a graft copolymer polymer consisting of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol, and is a carrier polymer for solid dispersions. The content ratio of polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol in the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer according to this embodiment is not particularly limited, but an example is 13:57:30 by weight. An example of such a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer is Soluplus (registered trademark, BASF).

[0133] The number average molecular weight of the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer according to this embodiment is not particularly limited, and may be, for example, 10,000 g / mol or more and 10,000,000 g / mol or less, 30,000 g / mol or more and 3,000,000 g / mol or less, 10,000 g / mol or more and 1,000,000 g / mol or less, or 30,000 g / mol or more and 300,000 g / mol or less.

[0134] Polyvinylpyrrolidone (also known as povidone, povidone, or polyvidone) is a polymer of N-vinyl-2-pyrrolidone.

[0135] Of these additional polymers, hydroxypropyl methylcellulose or a derivative thereof is preferred, more preferably at least one selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate, and most preferably hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0136] In the solid dispersion according to this embodiment, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer are contained within the solid dispersion. Preferably, these three components are dispersed throughout the solid dispersion, and more preferably, these three components are uniformly dispersed throughout the solid dispersion. In the solid dispersion according to the present disclosure, the peptide and the surfactant having a sugar fatty acid ester structure are preferably dispersed in the polymer, more preferably dispersed at a fine level, and most preferably dispersed at a molecular level.

[0137] The solid dispersion according to this embodiment refers to a semi-solid or solid substance in which target substances (e.g., the above-mentioned peptide, the surfactant having a sugar fatty acid ester structure, and the above-mentioned polymer) are dispersed together. From the viewpoint of improving solubility, the above-mentioned substances are usually uniformly dispersed in the solid dispersion, preferably uniformly dispersed at a fine level, more preferably uniformly dispersed at a fine level, and most preferably uniformly dispersed at a molecular level.

[0138] The method for forming the solid dispersion is not particularly limited, and examples thereof include a method of forming the solid dispersion by removing a certain amount or all of the solvent from a solution in which the substance is dissolved, and a method of mixing the solid substance while adding a certain amount of solvent. Specific examples include spray drying, freeze drying, precipitation, melt extrusion, and mixed grinding. Spray drying or freeze drying is preferred, spray drying or freeze drying is more preferred, and spray drying is most preferred. By using the spray drying method, the substance in the solid dispersion can be more uniformly dispersed, and the solubility of the substance (e.g., peptide) contained in the solid dispersion can be further improved. The solvent may be any solvent capable of dissolving or dispersing the peptide, surfactant, and copolymer, and may be, for example, one or more selected from the group consisting of water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, dimethyl sulfoxide, and tetrahydrofuran, preferably one or more selected from the group consisting of water, methanol, ethanol, acetone, ethyl acetate, acetonitrile, dimethyl sulfoxide, and tetrahydrofuran, more preferably one or more selected from the group consisting of methanol, ethanol, acetone, and ethyl acetate, and most preferably one or more selected from the group consisting of methanol, ethanol, and acetone. The solvent may be used alone, or a mixed solvent of two or more solvents may be used. When a mixed solvent containing two or more solvents is used, it may be, for example, a mixed solvent of water and one or more solvents selected from the group consisting of methanol, ethanol, and acetone, preferably a mixed solvent of water and one or more solvents selected from the group consisting of methanol, ethanol, and acetone, more preferably a mixed solvent containing two or more solvents selected from the group consisting of methanol, ethanol, and acetone, and most preferably a mixed solvent containing two or more solvents selected from the group consisting of methanol, ethanol, and acetone. The ratio of the mixed solvents can be set arbitrarily depending on the solubility of the peptide, surfactant, and polymer.

[0139] [Composition] The composition according to this embodiment consists of the solid dispersion or contains the solid dispersion. The composition according to this embodiment may be a pharmaceutical composition, and for example, the active ingredient may be a peptide. When the composition contains a solid dispersion, the content of the solid dispersion may be, for example, 30 to 99% by mass, preferably 50 to 99% by mass, more preferably 90 to 99% by mass, and most preferably 95 to 99% by mass, based on the total mass of the composition.

[0140] In the composition according to this embodiment, the ratio of the content of the peptide to the content of the surfactant having a sugar fatty acid ester structure is not particularly limited, but for example, the weight ratio of the content of the surfactant having a sugar fatty acid ester structure to the content of the peptide is from 0.1 to 40, preferably from 0.1 to 15.0, more preferably from 0.3 to 6.0, and most preferably from 0.5 to 3.0.

[0141] In the composition according to this embodiment, the ratio of the peptide content to the polymer content is not particularly limited, but the weight ratio of the polymer content to the peptide content is, for example, 0.6 to 20.0, preferably 0.8 to 15.0, more preferably 1.0 to 6.0, and most preferably 1.5 to 3.0.

[0142] When the composition according to this embodiment is a pharmaceutical composition, the pharmaceutical composition may contain other pharmaceutically acceptable ingredients to the extent that the effects of the present invention are not impaired. Examples of other ingredients include stabilizers, preservatives, antioxidants, disintegrants, excipients, binders, fluidizers, lubricants, etc. Stabilizers include phosphatidic acid, ascorbic acid, glycerin, cetyl alcohol, etc. Preservatives include ethyl parahydroxybenzoate and propyl parahydroxybenzoate, etc. Antioxidants include butylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl gallate, etc. Disintegrants include carmellose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, etc. Excipients include starches such as cornstarch, lactose, glucose, D-mannitol, etc. Binders include sucrose, gelatin, powdered acacia, methylcellulose, etc. Examples of the flow agent and lubricant include light anhydrous silicic acid, hydrous silicic acid dioxide, magnesium stearate, and talc.

[0143] When the composition according to this embodiment is a pharmaceutical composition, the content of other pharmaceutically acceptable components may be, for example, 1 to 99% by mass, preferably 1 to 75% by mass, more preferably 1 to 50% by mass, and most preferably 1 to 20% by mass, based on the total mass of the pharmaceutical composition.

[0144] When the composition according to the present embodiment is a pharmaceutical composition, the form of the pharmaceutical composition is not particularly limited, but is typically solid. The pharmaceutical composition is used after being formed into dosage forms such as powders, fine granules, granules, tablets, coated tablets, capsules, etc.

[0145] When the composition according to this embodiment is a pharmaceutical composition, the pharmaceutical composition may be administered orally or parenterally, and is preferably administered orally due to the enhanced solubility of the peptide.

[0146] When the composition according to this embodiment is a pharmaceutical composition, the subject to which the pharmaceutical composition is administered is not particularly limited and may be a human or a non-human animal, such as a dog, monkey, miniature pig, rabbit, rat, or mouse.

[0147] When the composition according to this embodiment is a pharmaceutical composition, the dosage of the pharmaceutical composition is not particularly limited, and may be administered so that the peptide dosage per kg of subject body weight (kg) is 0.1 mg / kg to 1000 mg / kg. The dosage of the peptide may be, for example, 1 mg / kg to 500 mg / kg, 1 mg / kg to 100 mg / kg, 1 mg / kg to 50 mg / kg, 3 mg / kg to 30 mg / kg, 10 mg / kg to 30 mg / kg, 0.1 mg / kg to 10 mg / kg, 1 mg / kg to 5 mg / kg, 10 mg / kg to 100 mg / kg, 15 mg / kg to 50 mg / kg, 20 mg / kg to 40 mg / kg, 25 mg / kg to 35 mg / kg, 3 mg / kg, or 30 mg / kg.

[0148] The composition according to this embodiment can be produced by molding into any dosage form using a conventional method.

[0149] [Evaluation and Use of Composition] The solubility of the peptide contained in the composition of this embodiment can be evaluated, for example, by adding the composition to a liquid to be dissolved and measuring the amount of dissolved peptide after incubation. The solution to be dissolved is not particularly limited, but when the composition is an oral pharmaceutical composition, it may be, for example, digestive fluid or an artificial solution prepared to mimic digestive fluid (artificial digestive fluid). The artificial digestive fluid may be, for example, artificial intestinal fluid and / or artificial gastric fluid. Examples of artificial intestinal fluids include the FaSSIF series (fasting small intestine, Biorelevant), the FeSSIF series (fed small intestine, Biorelevant), the Fasscof series (fasting large intestine, Biorelevant), and the Fasscof series (fed large intestine, Biorelevant). Examples of artificial gastric fluids include the FaSSGF series (fasting stomach, Biorelevant). The amount of dissolved peptide can be measured by a method commonly used by those skilled in the art, for example, by ultra-high performance liquid chromatography using a photodiode array detector, and may be calculated by an internal standard method.

[0150] The composition according to this embodiment can also be used as a pharmaceutical product containing a peptide as an active ingredient.

[0151] The composition according to this embodiment may contain the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer as a solid dispersion. In other words, in the composition according to this embodiment, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer may form a solid dispersion.

[0152] The composition according to this embodiment may contain the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer as a solid dispersion that is a spray-dried mixture containing the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer. In other words, in the composition according to this embodiment, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer may form a solid dispersion obtained by spray drying. Furthermore, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer in the composition according to this embodiment may be derived from a solid dispersion containing the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer. In other words, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer in the composition according to this embodiment may be supplied from a solid dispersion containing the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer. In other words, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer in the composition according to this embodiment may be contained in a solid dispersion containing the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer, or may be released from the solid dispersion in the composition.

[0153] Another embodiment of the present invention is a composition for producing a solid dispersion in combination with a peptide, the composition comprising a surfactant having a sugar fatty acid ester structure and a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester. The composition according to this embodiment is suitable for producing the solid dispersion according to the above embodiment by mixing the composition with a peptide and a solvent and then removing the solvent. The solvent removal step is not particularly limited, and examples include spray drying, freeze drying, precipitation, melt extrusion, and mixed grinding, with spray drying being preferred. The composition according to this embodiment may further contain a solvent, in which case it may be prepared in the form of a solution. The solvent may be any solvent that can dissolve or disperse the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer, and examples thereof include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. The solvent may be used alone or as a mixed solvent of two or more types.

[0154] Another embodiment of the present invention is a method for improving the solubility of a peptide, comprising combining a peptide, a surfactant having a sugar fatty acid ester structure, and a polymer comprising at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester. One aspect of this embodiment may comprise the steps of mixing a peptide, a surfactant having a sugar fatty acid ester structure, and a polymer comprising at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester together with a solvent to obtain a composition, and removing the solvent from the obtained composition. The composition may be a solution or dispersion. In one aspect of this embodiment, the peptide is represented by the following formula: The solvent may be a peptide (CP02) represented by the formula (I). The solvent may be any solvent capable of dissolving or dispersing the peptide, the surfactant having a sugar fatty acid ester structure, and the copolymer, and examples thereof include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. The solvent may be used alone or as a mixed solvent containing two or more solvents. The solvent removal process is not particularly limited, and examples thereof include spray drying, freeze drying, precipitation, melt extrusion, and mixed grinding, with spray drying being preferred.

[0155] Another embodiment of the present invention is a method for producing a composition, comprising a step of mixing a peptide, a surfactant having a sugar fatty acid ester structure, the surfactant, a polymer comprising at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester, and a solvent to obtain a composition (mixing step). The obtained composition may be a solution or dispersion. One aspect of this embodiment may further comprise a step of removing the solvent from the composition obtained in the mixing step (drying step). The solvent may be any solvent that can dissolve or disperse the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer, and examples thereof include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, and butanol), ketones (e.g., acetone, methyl ethyl ketone, and methyl isobutyl ketone), esters (e.g., ethyl acetate and propyl acetate), acetonitrile, methylene chloride, toluene, 1,1,1-trichloroethane, and tetrahydrofuran. The solvent may be used alone or as a mixed solvent of two or more kinds. The step of removing the solvent is not particularly limited, and includes spray drying, freeze drying, precipitation, melt extrusion, mixed grinding, etc., and is preferably spray drying. In one aspect of this embodiment, the composition obtained in the drying step may be the solid dispersion according to the above embodiment. In one aspect of this embodiment, the peptide is represented by the following formula: The peptide may be a peptide (CP02) represented by the formula:

[0156] In these embodiments, the definitions of the peptide, the surfactant having a sugar fatty acid ester structure, the polymer, and the solid dispersion can refer to those explained above. The composition produced by the production method according to this embodiment may be the composition according to one embodiment of the present invention.

[0157] The composition obtained in each of the above embodiments may be a solid dispersion. The solid dispersion contains a peptide, a surfactant having a sugar fatty acid ester structure, and the polymer. The polymer is present in a dispersed state throughout the solid dispersion, which differs from a coating in that the polymer is unevenly distributed on the surface. Such a solid dispersion can be produced by mixing a solvent with three components, namely, the peptide, the surfactant having a sugar fatty acid ester structure, and the polymer, to obtain a composition, and then removing the solvent.

[0158] The solid dispersions obtained in each of the above embodiments can be formulated into dosage forms such as powders, fine granules, granules, tablets, coated tablets, capsules, etc. In the case of powders, fine granules, and granules, the solid dispersion alone may be granulated, or excipients, lubricants, binders, stabilizers, preservatives, antioxidants, disintegrants, fluidizers, etc. may be further added before granulation. In the case of tablets, the solid dispersion itself may be molded by tableting, or excipients, lubricants, binders, stabilizers, preservatives, antioxidants, disintegrants, fluidizers, etc. may be further added before molding. In the case of capsules, the solid dispersion may be filled into empty capsules.

[0159] The present invention is further illustrated, but not limited, by the following examples. Unless otherwise noted, starting materials, starting materials, solvents, and reagents were obtained from commercial suppliers or synthesized using known methods.

[0160] In this specification, hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate, HPMCAS, hydroxypropyl methylcellulose, or one of its derivatives) was obtained from Shin-Etsu Chemical Co., Ltd. (Shin-Etsu AQOAT LF) and used. Eudragit L100, a copolymer of methyl methacrylate and methacrylic acid, was obtained from Evonik. Polyvinylpyrrolidone (PVP K30) and copovidone (Kollidon VA64) were obtained from BASF. The nonionic surfactant sucrose fatty acid ester (DK ester) was obtained from Daiichi Kogyo Seiyaku Co., Ltd. as DK ester SS (HLB value: approximately 19). FaSSIF, a simulated human fasting small intestine solution, was prepared by dissolving SIF powder obtained from BioRelevant in a phosphate buffer solution containing sodium chloride to a concentration of 3 mmol / L taurocholic acid and 0.75 mmol / L lecithin, and adjusting the pH to 6.5.

[0161] [Production Example 1] Production of cyclic peptides and crystals thereof The cyclic peptides CP01 to CP04 (corresponding to SEQ ID NOs: 1 to 4, respectively) used in this example are shown in Table 1. These compounds were synthesized according to the method described in WO 2021 / 090855. CP01: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-3-[2-[3-chloro-4-(trifluoromethyl)phenyl]ethyl]-30-cyclopentyl-10-ethyl-23-isobutyl-7,17,18,24,28,31-hexamethyl-20-[(1S)-1-methylpropyl]-27-(morpholine-4-carbonyl)-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-2,5,8,11,16,19,22,25,29,32,35-undecaone CP02: (3S,9S,12S,17S,20S,23S,27S,30S,36S)-30-Cyclopentyl-3-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-10-ethyl-23-isobutyl-N,N,7,17,18,24,28,31-octamethyl-20-[(1S)-1-methylpropyl]-2,5,8,11,16,19,22,25,29,32,35-undecaoxo-9-(p-tolylmethyl)spiro[1,4,7,10,15,18,21,24,28,31,34-undecazatricyclo[34.3.0.012,15]nonatriacontane-33,1'-cyclopentane]-27-carboxamide CP03: (2S,8S,12R,14S,20S,23S,27S,30S,36S,38Z)-20-cyclopentyl-8-[2-[3,5-difluoro-4-(trifluoromethyl)phenyl]ethyl]-12-ethoxy-27-isobutyl-N,N,4,19,22,26,32,35-octamethyl-30-[(1S)-1-methylpropyl]-3,6,9,15,18,21,25,28,31,34,42-undecaoxo-2-[[4-(trifluoromethyl)phenyl]methyl]spiro[1,4,7,10,16,19,22,26,29,32,35-undecazatricyclo[34.5.1.010,14]dotetracont-38-ene-17,1'-cyclopentane]-23-carboxamide CP04: (1S,4S,10S,13S,17S,20S,26S,28R,32S,38S,42Z)-20-cyclopentyl-28-ethoxy-32-[2-[3-methoxy-4-(trifluoromethyl)phenyl]ethyl]-N,N,2,14,18,21,24,36-octamethyl-10-[(1S)-1-methylpropyl]-3,9,12,15,19,22, 25,31,34,37,45-Undecaoxo-13-propyl-38-[[4-(trifluoromethyl)phenyl]methyl]spiro[2,8,11,14,18,21,24,30,33,36,39-undecazatetracyclo[37.5.1.04,8.026,30]pentatetracont-42-ene-23,1'-cyclobutane]-17-carboxamide.

[0162] The ClogP and molecular weight of peptides CP01 to CP04 are shown below. [ClogP] CP01: 14.899 CP02: 14.504 CP03: 15.204 CP04: 15.127 [Molecular weight] (unit: g / mol) CP01: 1478.2 CP02: 1437.7 CP03: 1547.7 CP04: 1553.8

[0163] [Evaluation Example] Evaluation of Solubility Unless otherwise specified, the solubility test of each sample obtained in each Example, Comparative Example, and Reference Example was carried out at 37°C, and the solubility under each condition was calculated by the internal standard method using ultra-high performance liquid chromatography with a photodiode array detector.

[0164] Unless otherwise specified, ultra high performance liquid chromatography in each example was carried out under the following conditions. Apparatus name: Waters ACQUITY UPLC H-Class Plus (manufactured by Waters) Column: ACQUITY UPLC BEH Shield RP18 Column, 130 Å, 1.7 μm, 2.1 × 50 mm (manufactured by Waters) Detector: ACQUITY UPLC PDA detector (manufactured by Waters) Mobile phase A: 0.05% trifluoroacetic acid / ultrapure water Mobile phase B: 0.05% trifluoroacetic acid / acetonitrile Sample temperature: 20°C Column temperature: 60°C Injection volume: 2 μL Absorption wavelength: 210 nm (for CP01 to CP04), 315 nm (for internal standard substance) Gradient table

[0165] Examples, Comparative Examples, and Reference Examples: Preparation and Evaluation of Pharmaceutical Compositions (Example 1, Comparative Examples 1-1, 1-2, 1-3, Reference Example 1) DMSO solutions (50 μL) prepared according to the compositions shown in Table 3 were lyophilized to prepare solid dispersions (samples) containing the cyclic peptide CP01. Lyophilization was performed using a dry chamber for a lyophilizer (EYELA DRC-1000). The samples were frozen at −40°C, then dried in a vacuum at −25°C for approximately 60 hours, and then returned to 25°C. Except for Reference Example 1, FaSSIF (50 μL) was added to each sample obtained, and the samples were shaken for 10 and 240 minutes, filtered, and the solubility was measured. In Reference Example 1, FaSSIF (50 μL) containing 0.5 mg / mL of DK ester SS was added, and the samples were shaken for 10 and 240 minutes, filtered, and the solubility was measured. These results are shown in Table 4.

[0166] The results of Example 1 and Comparative Examples 1-1 to 1-3 showed that a combination of DK ester SS and Eudragit L100 resulted in higher solubility than when combined with other polymers. Furthermore, the results of Reference Example 1 and Example 1 showed that the inclusion of a cyclic peptide, DK ester SS, and Eudragit L100 in a solid dispersion resulted in higher solubility than when DK ester SS was not included in the solid dispersion.

[0167]

[0168] (Example 2, Comparative Examples 2-1, 2-2, 2-3, Reference Example 2) Solubility was measured in the same manner as in Example 1, Comparative Examples 1-1, 1-2, 1-3, and Reference Example 1, except that CP01 was changed to CP02. The compositions of the prepared DMSO solutions are shown in Table 5, and the measured solubility results are shown in Table 6. The results in Table 6 demonstrate that even when the cyclic peptide was changed from CP01 to CP02, high solubility was achieved by combining DK ester SS and Eudragit L100 and by including these and the cyclic peptide as three components within the solid dispersion.

[0169] (Example 3, Comparative Examples 3-1, 3-2, 3-3, Reference Example 3) Except for changing CP01 to CP03, the solubility was measured in the same manner as in Example 1, Comparative Examples 1-1, 1-2, 1-3, and Reference Example 1. The compositions of the prepared DMSO solutions are shown in Table 7, and the measured solubility results are shown in Table 8.

[0170] The results shown in Table 8 indicate that even when the cyclic peptide was changed from CP01 to CP03, high solubility was obtained by combining DK ester SS and Eudragit L100 and containing the three components, namely, these and the cyclic peptide, inside the solid dispersion.

[0171] (Example 4, Comparative Examples 4-1, 4-2, 4-3, Reference Example 4) Except for changing CP01 to CP04, the solubility was measured in the same manner as in Example 1, Comparative Examples 1-1, 1-2, 1-3, and Reference Example 1. The compositions of the prepared DMSO solutions are shown in Table 9, and the measured solubility results are shown in Table 10.

[0172] The results shown in Table 10 indicate that even when the cyclic peptide was changed from CP01 to CP04, high solubility was obtained by combining DK ester SS and Eudragit L100 and containing the three components, namely, these and the cyclic peptide, inside the solid dispersion.

[0173] The results are shown in FIG.

[0174] (Example 5) An ethanol solution (stock solution) was prepared to have the same composition as in Example 4 and a solid concentration of 10 wt / vol%. This solution was spray-dried to prepare a solid dispersion (sample). Spray drying was carried out under the following conditions. The obtained sample was weighed out so that the CP04 content was 12.5 mg. The weighed sample was placed in a dissolution tester, and the solution was collected. The collected solution was diluted two-fold with a DMA solution in which 2-(1-naphthyl)ethanol, an internal standard, had been dissolved, and subjected to analysis by high-performance liquid chromatography. The dissolution test equipment and conditions used are shown in Table 11. Spray drying conditions Spray dryer: Mini-spray dryer (B-290, Buchi) (stock solution conditions) Solid component concentration: 10 wt / vol% (operating conditions) Inlet temperature: 87-88°C Outlet temperature: 49°C

[0175] The measured solubility results are shown in Table 13.

[0176] The conditions for high performance liquid chromatography in Example 5 are as follows: Apparatus name: Waters ACQUITY UPLC H-Class Plus (manufactured by Waters) Column: ACQUITY UPLC BEH Shield RP18 Column, 130 Å, 1.7 μm, 2.1 × 50 mm (manufactured by Waters) Detector: ACQUITY UPLC PDA detector (manufactured by Waters) Mobile phase A: 0.05% trifluoroacetic acid / ultrapure water Mobile phase B: 0.05% trifluoroacetic acid / acetonitrile Sample temperature: 20°C Column temperature: 40°C Injection volume: 1 μL Absorption wavelength: 278 nm (for CP04), 271 nm (for internal standard substance) Gradient table

[0177] The results shown in Table 13 indicate that changing freeze drying to spray drying results in fine, uniform particles, which in turn increases the wettability of the particles and therefore results in higher solubility.

[0178] (Example 6) DMSO solutions (50 μL) prepared according to the compositions shown in Table 14 were freeze-dried to prepare solid dispersions (samples) containing the cyclic peptide CP04. FaSSIF (50 μL) was added to each of the obtained samples, and the samples were shaken for 10 minutes and 240 minutes, then filtered and the solubility was measured. The results are shown in Table 15.

[0179] The results shown in Table 15 indicate that when the weight ratio of the polymer content to the peptide content is 0.6 or more, higher solubility is obtained than when the weight ratio is less than 0.6.

[0180]

Claims

1. A solid dispersion comprising (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, and (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester, wherein the weight ratio of the polymer content to the peptide content is 0.6 or more and 20.0 or less.

2. A method for producing a solid dispersion, comprising a step of removing the solvent from a mixture containing (1) a peptide, (2) a surfactant having a sugar fatty acid ester structure, (3) a polymer containing at least one selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester, and (4) a solvent, wherein the weight ratio of the polymer content to the peptide content is 0.6 or more and 20.0 or less.

3. The method according to claim 2, wherein the solvent is removed by spray drying.

4. The solid dispersion or method for producing the solid dispersion according to any one of claims 1 to 3, wherein the peptide has a cyclic portion.

5. The solid dispersion or method for producing a solid dispersion according to claim 4, wherein the number of amino acid residues constituting the cyclic portion is 5 to 15.

6. The solid dispersion or method for producing a solid dispersion according to any one of claims 1 to 5, wherein the peptide comprises one or more N-substituted amino acid residues.

7. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 6, wherein the HLB value of the surfactant is 1 to 20.

8. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 7, wherein the surfactant is a sucrose fatty acid ester.

9. The solid dispersion or the method for producing the solid dispersion according to any one of claims 1 to 8, wherein the proportion of monoester in the ester composition of the surfactant is 98% by weight or more.

10. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 9, wherein the fatty acid composition of the surfactant comprises at least one selected from the group consisting of palmitic acid and stearic acid.

11. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 10, wherein the proportion of stearic acid in the fatty acid composition of the surfactant is 50% by weight or more.

12. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 11, wherein the polymer is a polymer composed of a (meth)acrylic acid alkyl ester or a copolymer containing at least two selected from the group consisting of (meth)acrylic acid, a (meth)acrylic acid alkyl ester, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

13. The solid dispersion or method for producing a solid dispersion according to claim 12, wherein the copolymer is a copolymer comprising methyl methacrylate and methacrylic acid.

14. The solid dispersion or method for producing a solid dispersion according to any one of claims 1 to 13, wherein the ratio of the content of the surfactant to the content of the peptide is 0.1 or more and 15.0 or less by weight.

15. The solid dispersion or the method for producing a solid dispersion according to any one of claims 1 to 14, wherein the ratio of the content of the polymer to the content of the surfactant is 1.0 or more and 15.0 or less by weight.

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