Composition containing peptide, surfactant, and polymer

Abstract

Disclosed is a composition containing a peptide, a specific type of surfactant, and a specific type of polymer.

Description

Compositions Comprising Peptides, Surfactants, and Polymers

[0001] The present invention relates to a composition comprising a peptide, a surfactant and a 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] FutureMed. Chem., 2009, 1, 1289-1310.

[0005] In pharmaceutical compositions containing peptides as active ingredients, it is desirable that the solubility of the peptides be increased in order to ensure that the administered peptides exert their medicinal effects in the body with high efficiency.

[0006] To date, there have been no known cases in which the solubility of a peptide has been increased by combining a surfactant and a polymer, nor have there been any known cases in which the solubility of a peptide has been increased by combining a surfactant and a polymer without relying on the crystallization-inhibiting effect of the polymer.

[0007] An objective of the present invention is to provide a composition containing a peptide, in which the solubility of the peptide is enhanced.

[0008] The present inventors have found that a composition containing a peptide, a specific type of surfactant, and a specific type of polymer enhances the solubility of the peptide. Furthermore, the present inventors have found that such a composition enhances the solubility of the peptide without relying on the crystallization-inhibiting effect of the polymer.

[0009] The present invention relates to, for example, the following: [1] A composition comprising a solid dispersion which is a spray-dried product of a mixture comprising a peptide and one or more polymers selected from the group consisting of the following (IV) to (VIII), and one or more surfactants selected from the group consisting of the following (I) to (III): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropylmethylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester; (VI) copovidone; (VII) a polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone. [2] A composition which is a solid dispersion comprising a spray-dried mixture comprising a peptide and one or more polymers selected from the group consisting of the following (IV) to (VIII), and which is to be used in combination with one or more surfactants selected from the group consisting of the following (I) to (III): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.[3] A composition comprising one or more surfactants selected from the group consisting of the following (I) to (III), for use in combination with a solid dispersion which is a spray-dried product of a mixture comprising a peptide and one or more polymers selected from the group consisting of the following (IV) to (VIII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone. [4] A composition comprising a solid dispersion comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, and one or more surfactants selected from the group consisting of (I) to (III) below: (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [5] A composition in the form of a solid dispersion comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, for use in combination with one or more surfactants selected from the group consisting of (I) to (III) below: (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.[6] A composition comprising one or more surfactants selected from the group consisting of the following (I) to (III), for use in combination with a solid dispersion comprising a peptide and one or more polymers selected from the group consisting of the following (IV) and (VII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone. [7] A composition comprising a peptide (CP02) represented by the following formula, one or more surfactants selected from the group consisting of the following (I) to (III), and one or more polymers selected from the group consisting of the following (IV), (V), and (VII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [8] A composition comprising a peptide (CP02) represented by the following formula (IV), (V), and (VII), and for use in combination with one or more surfactants selected from the group consisting of the following formula (I) to (III): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. [9] A composition comprising one or more surfactants selected from the group consisting of the following (I) to (III), for use in combination with a peptide (CP02) represented by the following formula (I) and one or more polymers selected from the group consisting of the following (IV), (V), and (VII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[10] The composition according to any one of [1] to [9], which is a pharmaceutical composition.

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

[10] , wherein the molecular weight of the peptide is 500 g / mol or more and 5,000 g / mol or less.

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

[10] , wherein the molecular weight of the peptide is 1,000 g / mol or more and 2,000 g / mol or less.

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

[10] , wherein the molecular weight of the peptide is from 1,300 g / mol to 1,800 g / mol.

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

[10] , wherein the molecular weight of the peptide is from 1,400 g / mol to 1,600 g / mol.

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

[14] , wherein the number of amino acid residues constituting the peptide is from 5 to 30.

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

[14] , wherein the number of amino acid residues constituting the peptide is from 9 to 15.

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

[14] , wherein the number of amino acid residues constituting the peptide is from 10 to 14.

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

[14] , wherein the number of amino acid residues constituting the peptide is from 11 to 13.

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

[14] , wherein the number of amino acid residues constituting the peptide is 11.

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

[19] , wherein the peptide has a cyclic portion.

[21] The composition according to

[20] , wherein the cyclic portion comprises 5 to 15 amino acid residues.

[22] The composition according to

[20] , wherein the cyclic portion comprises 9 to 15 amino acid residues.

[23] The composition according to

[20] , wherein the number of amino acid residues constituting the cyclic portion is 10 to 14.

[24] The composition according to

[20] , wherein the number of amino acid residues constituting the cyclic portion is 11 to 13.

[25] The composition according to

[20] , wherein the number of amino acid residues constituting the cyclic portion is 11.

[26] The composition according to any one of

[20] to

[25] , wherein the cyclic portion consists of a 28- to 55-membered ring.

[27] The composition according to any one of

[20] to

[25] , wherein the cyclic portion consists of a 31- to 46-membered ring.

[28] The composition according to any one of

[20] to

[25] , wherein the cyclic portion consists of a 34- to 43-membered ring.

[29] The composition according to any one of

[20] to

[25] , wherein the cyclic portion consists of a 34- to 37-membered ring.

[30] The composition according to any one of

[20] to

[25] , wherein the cyclic portion consists of a 34-membered ring.

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

[30] , wherein the peptide contains one or more N-substituted amino acid residues.

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

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

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

[30] , wherein the peptide contains four or more N-substituted amino acid residues.

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

[30] , wherein the peptide contains five or more N-substituted amino acid residues.

[35] The nitrogen atom constituting the main chain of the N-substituted amino acid is C. １ -C ６ is substituted with alkyl, １ -C ６The composition according to any one of

[31] to

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

[36] The composition according to any one of

[31] to

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

[37] The composition according to any one of

[31] to

[34] , wherein the N-substituted amino acid is an N-methyl amino acid.

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

[37] , wherein the peptide comprises at least one β-amino acid backbone.

[39] The composition according to any one of

[20] to

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

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

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

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

[39] , wherein the peptide contains two or more N-unsubstituted amino acid residues.

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

[39] , wherein the peptide contains 3 or more N-unsubstituted amino acid residues.

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

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

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

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

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

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

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

[45] , wherein the peptide contains 0 to 3 aromatic rings.

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

[45] , wherein the peptide contains 1 to 3 aromatic rings.

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

[47] , wherein the peptide contains an acidic side chain, and the pKa of the acidic side chain is 3.5 to 10.

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

[47] , wherein, when the peptide has an acidic side chain, the pKa of the acidic side chain is 4.5 to 10.

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

[47] , wherein, when the peptide has an acidic side chain, the pKa of the acidic side chain is 5.0 to 10.

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

[50] , wherein, when the peptide has a basic side chain, the basic pKa of the basic side chain is 4.0 to 10.

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

[50] , wherein, when the peptide has a basic side chain, the basic pKa of the basic side chain is 4.0 to 9.0.

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

[50] , wherein, when the peptide has a basic side chain, the basic pKa of the basic side chain is 4.0 to 8.5.

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

[50] , wherein, when the peptide has a basic side chain, the basic pKa of the basic side chain is 4.0 to 7.5.

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

[50] , wherein, when the peptide has a basic side chain, the basic pKa of the basic side chain is 4.0 to 7.2.

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

[55] , wherein the ClogP of the peptide is 4 to 25.

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

[55] , wherein the ClogP of the peptide is 6 to 23.

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

[55] , wherein the ClogP of the peptide is 8 to 21.

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

[55] , wherein the ClogP of the peptide is 9 to 20.

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

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

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

[60] , wherein the peptide has a Clog P / amino acid residue ratio of 1.0 to 1.8.

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

[60] , wherein the peptide has a Clog P / amino acid residue ratio of 1.0 to 1.7.

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

[60] , wherein the peptide has a Clog P / amino acid residue ratio of 1.1 to 1.6.

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

[60] , wherein the peptide has a Clog P / amino acid residue ratio of 1.1 to 1.5.

[65] The composition according to any one of [1] to [6] and

[10] to

[64] , wherein the peptide is not a peptide described in (ECP1) to (ECP5) below.

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

[65] , wherein the surfactant is an anionic surfactant.

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

[65] , wherein the surfactant is sodium lauryl sulfate.

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

[65] , wherein the surfactant is an amphoteric surfactant.

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

[65] , wherein the surfactant is an acylcarnitine.

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

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

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

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

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

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

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

[65] , wherein the surfactant is polyoxyethylene hydrogenated castor oil.

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

[65] , wherein the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate.

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

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

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

[74] , wherein the polymer is an acidic polymer.

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

[76] , wherein the polymer is hydroxypropyl methylcellulose or a derivative thereof.

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

[76] , wherein the polymer is hydroxypropyl methylcellulose or an ester thereof.

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

[76] , wherein the polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methyl acetate maleate, and hydroxypropyl methyl trimellitate.

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

[76] , wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[76] , wherein the polymer is a copolymer of an alkyl (meth)acrylate ester and at least one monomer selected from the group consisting of (meth)acrylic acid, an alkyl (meth)acrylate ester, an alkylamino (meth)acrylate ester, and an ammonio alkyl (meth)acrylate ester.

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

[76] , wherein the polymer is a copolymer of an alkyl (meth)acrylate ester and at least one monomer selected from the group consisting of (meth)acrylic acid, an alkyl (meth)acrylate ester, and an alkylamino alkyl (meth)acrylate ester.

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

[76] , wherein the polymer is a copolymer of an alkyl (meth)acrylate ester and at least one monomer selected from the group consisting of (meth)acrylic acid and an alkylamino alkyl (meth)acrylate ester.

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

[76] , wherein the polymer is a copolymer of an alkyl (meth)acrylate ester and (meth)acrylic acid.

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

[76] , wherein the polymer is a copolymer of methyl methacrylate or ethyl acrylate and (meth)acrylic acid.

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

[76] , wherein the polymer is one or more selected from the group consisting of a copolymer of methyl methacrylate and methacrylic acid and a copolymer of ethyl acrylate and methacrylic acid.

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

[76] , wherein the polymer is a copolymer of methyl methacrylate and methacrylic acid.

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

[76] , wherein the polymer is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

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

[65] , wherein the surfactant is an anionic surfactant and the polymer is hydroxypropyl methylcellulose or a derivative thereof.

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

[65] , wherein the surfactant is sodium lauryl sulfate and the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[65] , wherein the surfactant is an anionic surfactant and the polymer is 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

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

[65] , wherein the surfactant is sodium lauryl sulfate and the polymer is a copolymer of methyl methacrylate and methacrylic acid.

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

[65] , wherein the surfactant is an amphoteric surfactant and the polymer is hydroxypropyl methylcellulose or a derivative thereof.

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

[65] , wherein the surfactant is lauroyl-L-carnitine and the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[65] , wherein the surfactant is an amphoteric surfactant and the polymer is 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

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

[65] , wherein the surfactant is lauroyl-L-carnitine and the polymer is a copolymer of methyl methacrylate and methacrylic acid.

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

[65] , wherein the surfactant is a nonionic surfactant and the polymer is hydroxypropyl methylcellulose or a derivative thereof.

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

[65] , wherein the surfactant is a sucrose fatty acid ester and the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[65] , wherein the surfactant is polyoxyethylene hydrogenated castor oil and the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[65] , wherein the surfactant is D-α-tocopherol polyethylene glycol 1000 succinate and the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

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

[65] , wherein the surfactant is an anionic surfactant and the polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

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

[65] , wherein the surfactant is sodium lauryl sulfate and the polymer is polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

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

[102] , wherein the content of the surfactant relative to the content of the peptide is a weight ratio of 0.1 to 40.0.

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

[102] , wherein the content of the surfactant relative to the content of the peptide is a weight ratio of 0.1 to 15.0.

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

[102] , wherein the content of the surfactant relative to the content of the peptide is a weight ratio of 0.3 to 6.0.

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

[102] , wherein the content of the surfactant relative to the content of the peptide is a weight ratio of 0.5 to 3.0.

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

[106] , wherein the weight ratio of the content of the polymer to the content of the peptide is 0.01 to 40.0.

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

[106] , wherein the weight ratio of the content of the polymer to the content of the peptide is 0.01 to 15.0.

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

[106] , wherein the weight ratio of the content of the polymer to the content of the peptide is 0.03 to 6.0.

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

[106] , wherein the weight ratio of the content of the polymer to the content of the peptide is 0.1 to 3.0.

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

[110] , wherein the ratio of the solubility of the peptide when a composition consisting of the peptide, the surfactant, the polymer, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 to the sum of the solubility of the peptide when a composition consisting of the peptide, the surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 is greater than 1.0.

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

[110] , wherein the ratio of the solubility of the peptide when a composition consisting of the peptide, the surfactant, the polymer, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 to the sum of the solubility of the peptide when a composition consisting of the peptide, the surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 and the solubility of the peptide when a composition consisting of the peptide, the surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 exceeds 1.3.

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

[110] , wherein the ratio of the solubility of the peptide when a composition comprising the peptide, the surfactant, the polymer, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 to the sum of the solubility of the peptide when a composition comprising the peptide, the surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 and the solubility of the peptide when a composition comprising the peptide, the surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 exceeds 1.5.

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

[113] , wherein the peptide is in an amorphous form.

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

[113] , wherein the peptide is in a crystalline form.

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

[113] , wherein the composition is for improving the solubility of the peptide.

[117] The composition according to

[116] , wherein the improvement in the solubility of the peptide is improvement in the solubility of the peptide in both an amorphous state and a crystalline state.

[118] A composition containing a peptide used in the presence of one or more surfactants selected from the group consisting of the following (I) to (III) and one or more polymers selected from the group consisting of the following (IV) to (VIII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.

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

[118] , wherein the active ingredient is the peptide.

[120] The composition according to any one of [7] to

[119] , wherein the peptide and the polymer form a solid dispersion.

[121] The composition according to any one of [4] to [6] and

[10] to

[120] , wherein the solid dispersion is a spray-dried product.

[122] A method for producing a composition, comprising a step of combining a solid dispersion that is a spray-dried product of a mixture containing a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below with one or more surfactants selected from the group consisting of (I) to (III) below to obtain a composition: (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.

[123] The method according to

[122] , further comprising a step of removing the solvent from the solution containing the peptide and the polymer to obtain a solid dispersion.

[124] The production method according to

[122] , further comprising a step of spray-drying a mixture containing the peptide and the polymer to obtain a solid dispersion.

[125] A method for producing a composition, comprising a step of combining a solid dispersion containing a peptide and one or more polymers selected from the group consisting of the following (IV) and (VII), with one or more surfactants selected from the group consisting of the following (I) to (III), to obtain a composition: (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[126] A method for producing a composition, comprising a step of combining a peptide (CP02) represented by the following formula, one or more surfactants selected from the group consisting of the following (I) to (III), and one or more polymers selected from the group consisting of the following (IV), (V), and (VII), to obtain a composition: (I) anionic surfactants; (II) amphoteric surfactants; (III) nonionic surfactants; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; and (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[127] A method for improving the solubility of a peptide by combining a solid dispersion, which is a spray-dried product of a mixture containing the peptide and one or more polymers selected from the group consisting of the following (IV) to (VIII), with one or more surfactants selected from the group consisting of the following (I) to (III): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropylmethylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester; (VI) copovidone; (VII) polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.

[128] A method for improving the solubility of a peptide by combining a solid dispersion containing the peptide and one or more polymers selected from the group consisting of the following (IV) and (VII), with one or more surfactants selected from the group consisting of the following (I) to (III): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropylmethylcellulose or a derivative thereof; (VII) a polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

[129] A method for improving the solubility of a peptide (CP02) represented by the following formula, by combining the peptide with one or more surfactants selected from the group consisting of the following (I) to (III), and one or more polymers selected from the group consisting of the following (IV), (V), and (VII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[130] The method for improving solubility of the peptide according to any one of

[127] to

[129] , wherein the improvement in solubility of the peptide is an improvement in solubility of the peptide in both an amorphous state and a crystalline state.

[131] Use or application of one or more surfactants selected from the group consisting of the following (I) to (III) as a solubility enhancer for a peptide present in a solid dispersion which is a spray-dried product of a mixture comprising a peptide and one or more polymers selected from the group consisting of the following (IV) to (VIII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.

[132] Use or application of one or more surfactants selected from the group consisting of the following (I) to (III) as a solubility enhancer for a peptide present in a solid dispersion comprising a peptide and one or more polymers selected from the group consisting of the following (IV) and (VII): (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropylmethylcellulose or a derivative thereof; (VII) polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer.

[133] Use or application of a combination of one or more surfactants selected from the group consisting of the following (I) to (III) and one or more polymers selected from the group consisting of the following (IV), (V) and (VII) as a solubility improver for a peptide (CP02) represented by the following formula: (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[134] The use or application according to any one of

[131] to

[133] , wherein the improvement in solubility of the peptide is improvement in solubility of the peptide in both an amorphous state and a crystalline state.

[0010] According to the present invention, a composition containing a peptide can be provided in which the solubility of the peptide is enhanced.

[0011] According to the present invention, it is possible to provide a composition containing a peptide in which the solubility of the peptide is increased without relying on the crystallization-inhibiting effect of a polymer.

[0012] According to the present invention, it is possible to provide a composition containing a peptide in which a surfactant and a polymer exhibit a synergistically enhanced solubilizing effect, thereby increasing the solubility of the peptide.

[0013] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] As used herein, "DMSO" means dimethyl sulfoxide.

[0019] In this specification, "wt / vol %" represents weight / volume %.

[0020] The composition according to this embodiment comprises a peptide, one or more surfactants selected from the group consisting of (I) to (III) below, and one or more polymers selected from the group consisting of (IV) to (VIII) below. In one aspect, the composition according to this embodiment comprises a solid dispersion that is a spray-dried product of a mixture comprising a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below, and one or more surfactants selected from the group consisting of (I) to (III) below. In one aspect, the composition according to this embodiment comprises a solid dispersion comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, and one or more surfactants selected from the group consisting of (I) to (III) below. In one aspect, the composition according to this embodiment comprises a peptide having a structure represented by the following formula: The composition according to this embodiment comprises a peptide (CP02) represented by the formula (I), one or more surfactants selected from the group consisting of the following (I) to (III), and one or more polymers selected from the group consisting of the following (IV), (V), and (VII). The composition according to this embodiment is preferably a pharmaceutical composition. (I) an anionic surfactant; (II) an amphoteric surfactant; (III) a nonionic surfactant; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone

[0021] [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.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] As used herein, "amino acid" includes natural amino acids and unnatural amino acids (sometimes referred to as amino acid derivatives). Furthermore, as used herein, "amino acid residue" includes natural amino acid residues and unnatural amino acid (amino acid derivative) residues.

[0026] 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).

[0027] 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.

[0028] As used herein, amino acids are allowed to have any steric configuration. The side chain of an amino acid is not particularly limited, and in addition to a hydrogen atom, it can be freely selected from, for example, alkyl groups, alkenyl groups, alkynyl groups, aryl groups, heteroaryl groups, aralkyl groups, heteroaralkyl groups, cycloalkyl groups, and spiro-linked cycloalkyl groups. Each of these groups may be substituted, and the substituents are not limited. For example, one or more of these 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., as well as 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).

[0029] 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 , hereinafter referred to as “C 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 (2-methylpropyl), n-pentyl, s-pentyl (1-methylbutyl), t-pentyl (1,1-dimethylpropyl), neopentyl (2,2-dimethylpropyl), isopentyl (3-methylbutyl), 3-pentyl (1-ethylpropyl), 1,2-dimethylpropyl, 2-methylbutyl, n-hexyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1,1,2,2-tetramethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, and 2-ethylbutyl.

[0030] 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.

[0031] 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.

[0032] 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).

[0033] 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 (5- to 10-membered heteroaryl), and more preferably 5 to 7 (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.

[0034] As used herein, "aralkyl (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.

[0035] As used herein, "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 -C ２Specific 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.

[0036] 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.

[0037] 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.

[0038] 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, a monoC １ -C ６Specific examples of monoalkylamino include methylamino, ethylamino, n-propylamino, i-propylamino, n-butylamino, s-butylamino, and t-butylamino.

[0039] 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.

[0040] As used herein, "alkylsulfonylamino" refers to a group in which a sulfonyl group is bonded to the "amino" defined above. １ -C ６ Alkylsulfonyl-NH-, (C １ -C ６ Alkylsulfonyl-) ２ Specific examples of the aminoalkylsulfonyl include methylsulfonylamino, ethylsulfonylamino, bis(methylsulfonyl)amino, bis(ethylsulfonyl)amino, and the like.

[0041] As used herein, "aminocarbonyl" refers to a carbonyl group to which the above-defined "amino" is bonded. As the aminocarbonyl, -CONH is preferable. ２ , Mono C １ -C ６ Alkylaminocarbonyl, diC １ -C ６ Examples of the aminocarbonyl include alkylaminocarbonyl and 4- to 8-membered cyclic aminocarbonyl. Specific examples of the 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.

[0042] Halogen-derived substituents include fluoro (-F), chloro (-Cl), bromo (-Br), iodo (-I), and the like.

[0043] 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).

[0044] Examples of oxy (—OR) include alkoxy, cycloalkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, aralkyloxy, and the like.

[0045] Examples of carbonyl (-C(=O)-R) include formyl (-C(=O)-H), alkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, heteroarylcarbonyl, aralkylcarbonyl, and the like.

[0046] Examples of oxycarbonyl (-C(=O)-OR) include alkyloxycarbonyl, cycloalkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkyloxycarbonyl, and the like.

[0047] Examples of carbonyloxy (—O—C(═O)—R) include alkylcarbonyloxy, cycloalkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, aralkylcarbonyloxy, and the like.

[0048] Examples of thiocarbonyl (-C(=O)-SR) include alkylthiocarbonyl, cycloalkylthiocarbonyl, alkenylthiocarbonyl, alkynylthiocarbonyl, arylthiocarbonyl, heteroarylthiocarbonyl, aralkylthiocarbonyl, and the like.

[0049] Examples of carbonylthio (-S-C(=O)-R) include alkylcarbonylthio, cycloalkylcarbonylthio, alkenylcarbonylthio, alkynylcarbonylthio, arylcarbonylthio, heteroarylcarbonylthio, aralkylcarbonylthio, and the like.

[0050] 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.

[0051] 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] Examples of thio (-S-R) include alkylthio, cycloalkylthio, alkenylthio, alkynylthio, arylthio, heteroarylthio, aralkylthio, and the like.

[0058] Examples of sulfinyl (-S(=O)-R) include alkylsulfinyl, cycloalkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, arylsulfinyl, heteroarylsulfinyl, aralkylsulfinyl, and the like.

[0059] Sulfonyl (-S(O) ２ Examples of —R) include alkylsulfonyl, cycloalkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, and the like.

[0060] 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.

[0061] Examples of secondary amino (-NH-R) include alkylamino, cycloalkylamino, alkenylamino, alkynylamino, arylamino, heteroarylamino, and aralkylamino.

[0062] 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.

[0063] 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.

[0064] 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.

[0065] 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.

[0066] 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.

[0067] The main chain amino group of the amino acid is unsubstituted (-NH ２ ) or may be substituted (i.e., —NHR, where R represents, for example, an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, aralkyl group, 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).

[0068] 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" refers to a peptide having a cyclic structure composed of four or more amino acid residues. The cyclization of a 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.

[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] "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-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 a 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 backbone of the amino acids 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 backbone, etc.

[0071] As used herein, the "cyclic portion" of a cyclic peptide refers to a cyclic portion formed by linking four or more amino acid residues.

[0072] 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.

[0073] 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.

[0074] As used herein, the term "N-substituted amino acid" refers to an amino acid in which the amino group contained therein is substituted, that is, -NHR (R represents alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, or cycloalkyl 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.

[0075] 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.

[0076] 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, or 5 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.

[0077] 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.

[0078] 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.

[0079] In this specification, the "amino acid residues" that constitute a peptide may be simply referred to as "amino acids".

[0080] 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 carboxyl 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 carboxyl group bonded to the α-carbon, can serve as the side chain of an amino acid.

[0081] As used herein, the term "amino acid main chain" refers to the chain portion composed of an amino group, an α-carbon, and a carboxyl group in the case of an α-amino acid; the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group in the case of a β-amino acid; and the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group in the case of a γ-amino acid. Furthermore, the term "α-amino acid backbone" refers to the chain portion composed of an amino group, an α-carbon, and a carboxyl group; the term "β-amino acid backbone" refers to the chain portion composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group; and the term "γ-amino acid backbone" refers to the chain portion composed of an amino group, a γ-carbon, a β-carbon, an α-carbon, and a carboxyl group. As used herein, amino acids having a "β-amino acid backbone" as their entire or partial structure may be referred to as "amino acids having a β-amino acid backbone." For example, L-aspartic acid has a chain portion (β-amino acid skeleton) composed of an amino group, a β-carbon, an α-carbon, and a carboxyl group, and therefore falls under the category of "amino acids having a β-amino acid skeleton."

[0082] The peptide in this embodiment may contain at least one β-amino acid backbone, and preferably contains at least one β-amino acid backbone.

[0083] 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.

[0084] As used herein, the term "substituted hydroxyphenyl group" refers to a group in which at least one hydrogen atom on the aromatic ring of a hydroxyphenyl group is substituted 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 the hydrogen atoms of the aromatic ring in this specification 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.

[0085] 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."

[0086] In this specification, "having no substituted or unsubstituted XX group" means having neither a substituted XX group nor an unsubstituted XX group.

[0087] 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.

[0088] 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 compound, 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.

[0089] 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.

[0090] As used herein, pKa refers to the measured pKa unless otherwise specified. Furthermore, a pKa value determined using the ADMET Predictor described below is referred to as the calculated pKa. As used herein, Basic pKa refers to the measured Basic pKa unless otherwise specified. Furthermore, a Basic pKa value determined using the ADMET Predictor described below is referred to as the calculated Basic pKa.

[0091] The pKa and basic pKa can be measured by conventional methods. For example, they can be measured by the method described in Experimental Chemistry Lectures 5, "Thermal Measurement and Equilibrium," p. 460 (edited by the Chemical Society of Japan, published by Maruzen Co., Ltd.). Furthermore, when the pKa value and basic pKa value of the side chain of the amino acid to be measured are difficult to determine due to the influence of other functional groups, the other functional groups can be appropriately protected with protecting groups or the like so that only the pKa and basic pKa of the target functional group can be measured.

[0092] As used herein, an "acidic side chain" refers to a side chain having a pKa of 10 or less, and a "basic side chain" refers to a side chain having a basic pKa of 4 or more. As used herein, a side chain having a pKa of more than 10 or a side chain having a basic pKa of less than 4 is defined as a neutral side chain.

[0093] In this specification, the calculated pKa and Basic calculated pKa of the side chain of an amino acid or the side chain of the cyclic portion of a cyclic peptide compound can be determined using ADMET Predictor (Simulations Plus Inc., ver. 8.0). The calculated pKa and Basic calculated pKa are calculated using a partial structure obtained by extracting the side chain portion from the side chain β-position (carbon directly attached to the main chain). As an example, the case of Lys is shown below. The Basic calculated pKa was calculated to be 10.5 using a partial structure including the side chain β-position (carbon directly attached to the main chain). Similarly, for acids, the calculated pKa of the side chain carboxy group of Asp was 4.3, the calculated pKa of the side chain phenolic hydroxyl group of Tyr was 9.9, the calculated pKa of the side chain phenolic hydroxyl group of 3-fluorotyrosine (Tyr(3-F)) was 8.7, and the calculated pKa of tetrazole was 3.7. On the other hand, as for bases, the calculated basic pKa of the side chain guanidino group of Arg was 12.7, the calculated basic pKa of the imidazolyl group of His was 7.6, and the calculated basic pKa of pyridine was 5.4.

[0094] When the peptide of this embodiment has an acidic side chain, the pKa of the acidic side chain is not particularly limited, and may be, for example, 3.5 or more, 4.0 or more, 4.5 or more, or 5.0 or more, or 10 or less. When the peptide of this embodiment has an acidic side chain, the pKa of the acidic side chain is not particularly limited, and may be, for example, 3.5 to 10, 4.0 to 10, 4.5 to 10, or 5.0 to 10. When the peptide of this embodiment has an acidic side chain, the pKa of the acidic side chain is not particularly limited, and may be, for example, 3.5 to 10, preferably 4.0 to 10, more preferably 4.5 to 10, and most preferably 5.0 to 10.

[0095] When the peptide of this embodiment has a basic side chain, the basic pKa of the basic side chain is not particularly limited, and may be, for example, 4.0 or higher, 10 or lower, 9.0 or lower, 8.5 or lower, 8.0 or lower, 7.5 or lower, or 7.2 or lower. When the peptide of this embodiment has a basic side chain, the basic pKa of the basic side chain is not particularly limited, and may be, for example, 4.0 to 10, 4.0 to 9.0, 4.0 to 8.5, 4.0 to 8.0, 4.0 to 7.5, or 4.0 to 7.2. When the peptide of this embodiment has a basic side chain, the basic pKa of the basic side chain is not particularly limited, and may be, for example, 4.0 to 10, preferably 4.0 to 8.5, more preferably 4.0 to 7.5, and most preferably 4.0 to 7.2.

[0096] As used herein, "ClogP" refers to a computer-calculated partition coefficient. ClogP can be calculated in accordance with the principles described in Daylight Version 4.9 (https: / / www.daylight.com / dayhtml / doc / clogp / ) from Daylight Chemical Information Systems, Inc. As an example of a method for calculating ClogP, the following method is used: Examples of calculations include using Daylight Version 4.95 (release date: August 1, 2011, ClogP algorithm version 5.4, database version 28, https: / / www.daylight.com / dayhtml / doc / release_notes / index.html) by Yahoo!

[0097] 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.

[0098] In this embodiment, the ClogP of the peptide is not particularly limited, but may be, for example, equal to or greater than the peptide (CP02) shown below.

[0099] As used herein, "ClogP / number of amino acid residues" refers to a value calculated by dividing the ClogP of a peptide compound by the number of amino acid residues contained in the peptide compound. For example, if the ClogP of a peptide compound is 14.0 and the number of amino acid residues contained in the peptide compound is 7, the ClogP / number of amino acid residues of the peptide compound is calculated to be 2.0.

[0100] 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.

[0101] In this embodiment, the peptide is not particularly limited, but may exclude, for example, the peptides described in (ECP1) to (ECP5) below.

[0102] In this embodiment, the peptide may be in an amorphous form. Also, in this embodiment, the peptide may be in a crystalline form.

[0103] [Surfactant] In this embodiment, the surfactant is one or more selected from the group consisting of the following (I) to (III). In this embodiment, the surfactant is preferably one or more selected from the group consisting of the following (I) and (II): (I) Anionic surfactant (II) Amphoteric surfactant (III) Nonionic surfactant

[0104] In one preferred aspect of this embodiment, the surfactant may be, for example, an anionic surfactant, preferably an alkyl sulfate, more preferably lauryl sulfate, and most preferably sodium lauryl sulfate (also known as sodium dodecyl sulfate).

[0105] 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.

[0106] In another preferred aspect of this embodiment, the surfactant may be, for example, an amphoteric surfactant, preferably an acylcarnitine, more preferably lauroylcarnitine, and most preferably lauroyl-L-carnitine.

[0107] The amphoteric surfactant in this embodiment is not particularly limited, but examples thereof 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. The acylcarnitine is preferably lauroylcarnitine or carnitine palmitate, more preferably lauroylcarnitine, and most preferably lauroyl-L-carnitine.

[0108] 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, sucrose 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.

[0109] Of all these surfactants, anionic surfactants are preferred, lauryl sulfate is more preferred, and sodium lauryl sulfate is most preferred.

[0110] [Polymer] In this embodiment, the polymer is selected from the group consisting of the following (IV) to (VIII): (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone

[0111] When the composition according to one aspect of this embodiment contains a peptide as a solid dispersion that is a spray-dried mixture of the peptide and a polymer, the polymer may be one or more selected from the group consisting of (IV) to (VII) above, preferably one or more selected from the group consisting of (IV), (V), and (VII), more preferably one or more selected from the group consisting of (IV) and (V), and most preferably (IV). Use of these polymers can efficiently increase the solubility of the peptide.

[0112] When the composition according to one aspect of this embodiment contains a peptide as a solid dispersion of a mixture of the peptide and a polymer, the polymer may be one or more selected from the group consisting of (IV) and (VII) above, preferably one or more selected from the group consisting of (IV) and (VII), more preferably (IV), and most preferably (IV). Use of these polymers can efficiently increase the solubility of the peptide.

[0113] In one aspect of this embodiment, the peptide has the formula: In the case of peptide (CP02) represented by the formula (IV), (V), and (VII), the polymer may be one or more polymers selected from the group consisting of (IV), (V), and (VII), preferably one or more polymers selected from the group consisting of (IV) and (VII), more preferably one or more polymers selected from the group consisting of (IV) and (VII), and preferably (IV). By using these polymers, the solubility of CP02 can be efficiently increased.

[0114] The polymers according to this embodiment may be used alone or in combination of two or more.

[0115] In this embodiment, the polymer is preferably an ionic polymer, more preferably an acidic polymer.

[0116] 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.

[0117] 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, polyvinyl alcohol acetate phthalate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl methacrylate copolymer, copolymer of acrylic acid and methacrylic acid, copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid, copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid alkylamino alkyl ester, and copolymer of (meth)acrylic acid alkyl ester and (meth)acrylic acid ammonio alkyl ester.

[0118] In this embodiment, examples of the basic polymer include aminoalkyl methacrylic acid copolymer E and polyvinyl acetal diethylamino acetate.

[0119] In a preferred aspect of this embodiment, the polymer may be, for example, hydroxypropyl methylcellulose or a derivative thereof, preferably hydroxypropyl methylcellulose or an ester thereof, more preferably one or more 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).

[0120] 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.

[0121] In the present embodiment, the hydroxypropyl methylcellulose or derivative thereof is not particularly limited, but is preferably hydroxypropyl methylcellulose or an ester thereof, more preferably one or more 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).

[0122] In one aspect of this embodiment, the polymer may be, for example, 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, a (meth)acrylic acid alkylaminoalkyl ester, and a (meth)acrylic acid ammonioalkyl ester; 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; more preferably a copolymer of a (meth)acrylic acid alkyl ester and at least one monomer selected from the group consisting of (meth)acrylic acid and a (meth)acrylic acid alkylaminoalkyl ester; and most preferably a copolymer of a (meth)acrylic acid alkyl ester and (meth)acrylic acid. In this case, the copolymer of a (meth)acrylic acid alkyl ester and (meth)acrylic acid is preferably one or more selected from the group consisting of a copolymer of methyl methacrylate and methacrylic acid and a copolymer of ethyl acrylate and methacrylic acid, and is more preferably a copolymer of methyl methacrylate and methacrylic acid. When a (meth)acrylic acid alkyl ester and a (meth)acrylic acid alkyl ester are combined, the combination is a combination of different alkyl esters or a combination of a methacrylic acid alkyl ester and an acrylic acid alkyl ester.

[0123] In this specification, the term "(meth)acrylic acid" means "acrylic acid and / or methacrylic acid."

[0124] The (meth)acrylic acid in this embodiment is not particularly limited, but is preferably methacrylic acid.

[0125] 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.

[0126] 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.

[0127] 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 ([(meth)acryloyloxyalkyl]trialkylammonium chloride), and is preferably trimethylammonium ethyl methacrylic acid chloride ([2-(methacryloyloxy)ethyl]trimethylammonium chloride).

[0128] In the copolymer of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, an alkyl (meth)acrylate, an alkylamino (meth)acrylate, and an ammonio alkyl (meth)acrylate, the ratio of the units derived from the alkyl (meth)acrylate to the units derived from at least one monomer selected from the group consisting of (meth)acrylic acid, an alkyl (meth)acrylate, an alkylamino alkyl (meth)acrylate, and an ammonio alkyl (meth)acrylate is not particularly limited, and 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.

[0129] 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.

[0130] 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.

[0131] 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).

[0132] 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.

[0133] Polyvinylpyrrolidone (also known as povidone, povidone, or polyvidone) is a polymer of N-vinyl-2-pyrrolidone.

[0134] Of all these polymers, hydroxypropyl methylcellulose or a derivative thereof is preferred, more preferably one or more 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).

[0135] [Combination of Surfactant and Polymer] In a preferred aspect of this embodiment, the surfactant may be an anionic surfactant, and the polymer may be hydroxypropylmethylcellulose or a derivative thereof.

[0136] In one preferred aspect of this embodiment, the surfactant may be sodium lauryl sulfate and the polymer may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0137] In a preferred aspect of this embodiment, the surfactant is an anionic surfactant, and the polymer may be 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

[0138] In one preferred aspect of this embodiment, the surfactant may be sodium lauryl sulfate and the polymer may be a copolymer of methyl methacrylate and methacrylic acid.

[0139] In a preferred aspect of this embodiment, the surfactant may be an amphoteric surfactant, and the polymer may be hydroxypropylmethylcellulose or a derivative thereof.

[0140] In one preferred aspect of this embodiment, the surfactant may be lauroyl-L-carnitine and the polymer may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0141] In a preferred aspect of this embodiment, the surfactant is an amphoteric surfactant, and the polymer may be 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester.

[0142] In one preferred aspect of this embodiment, the surfactant may be lauroyl-L-carnitine, and the polymer may be a copolymer of methyl methacrylate and methacrylic acid.

[0143] In a preferred aspect of this embodiment, the surfactant may be a nonionic surfactant, and the polymer may be hydroxypropylmethylcellulose or a derivative thereof.

[0144] In a preferred aspect of this embodiment, the surfactant may be a sucrose fatty acid ester, and the polymer may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0145] In a preferred aspect of this embodiment, the surfactant may be polyoxyethylene hydrogenated castor oil, and the polymer may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0146] In a preferred aspect of this embodiment, the surfactant may be D-α-tocopherol polyethylene glycol 1000 succinate, and the polymer may be hydroxypropyl methylcellulose acetate succinate (HPMCAS).

[0147] In a preferred aspect of this embodiment, the surfactant may be an anionic surfactant, and the polymer may be a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0148] In one preferred aspect of this embodiment, the surfactant may be sodium lauryl sulfate, and the polymer may be polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0149] [Composition] In the composition according to this embodiment, the ratio of the peptide content to the surfactant content is not particularly limited, but for example, the weight ratio of the surfactant content to the peptide content 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.

[0150] In the composition according to this embodiment, the ratio of the peptide content to the polymer content is not particularly limited, but for example, the weight ratio of the polymer content to the peptide content is from 0.01 to 40, preferably from 0.01 to 15.0, more preferably from 0.03 to 6.0, and most preferably from 0.1 to 3.0.

[0151] 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 / lubricant include light anhydrous silicic acid, hydrous silicic acid dioxide, magnesium stearate, and talc.

[0152] 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.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] The composition according to this embodiment can be produced by molding into any dosage form using a conventional method.

[0157] [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, a digestive fluid or an artificial solution prepared to mimic a 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.

[0158] In a specific example of evaluating the solubility of a peptide in a composition according to this embodiment, the composition or a control composition may be added to FaSSIF at pH 6.5 at 37°C, incubated, and then undissolved peptide removed by filtration. The solubility of the peptide may then be calculated by an internal standard method using ultra-high performance liquid chromatography with a photodiode array detector. For example, when the composition is a composition consisting of a peptide, a surfactant, a polymer, and DMSO, the target composition may be, for example, a composition consisting of a peptide, a polymer, and DMSO, or a composition consisting of a peptide, a surfactant, and DMSO. In this case, the solubility can be evaluated as being enhanced when the ratio of the solubility of the peptide when a composition comprising a peptide, a surfactant, a polymer, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 to the sum of the solubility of the peptide when a composition comprising a peptide, a polymer, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 and the solubility of the peptide when a composition comprising a peptide, a surfactant, and DMSO is dissolved in FaSSIF at 37°C and pH 6.5 is higher. For example, the solubility can be evaluated as being enhanced when this ratio exceeds 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, or 2.3.

[0159] The composition according to the present embodiment contains a peptide, a surfactant, and a polymer, thereby enhancing the solubility of the peptide in body fluids. The ratio of the solubility of the peptide when the composition comprising the peptide, surfactant, polymer, and DMSO is dissolved in FaSSIF at pH 6.5 at 37°C to the sum of the solubility of the peptide when the composition comprising the peptide, surfactant, and DMSO is dissolved in FaSSIF at pH 6.5 at 37°C is preferably greater than 1.0, more preferably greater than 1.3, and even more preferably greater than 1.5.

[0160] The composition according to this embodiment can be used as a pharmaceutical product containing a peptide as an active ingredient.

[0161] The composition according to this embodiment may contain the peptide and the polymer as a solid dispersion. In other words, in the composition according to this embodiment, the peptide and the polymer may form a solid dispersion.

[0162] The composition according to this embodiment may contain the peptide and polymer as a solid dispersion, which is a spray-dried mixture containing the peptide and polymer. In other words, in the composition according to this embodiment, the peptide and polymer may form a solid dispersion obtained by spray drying. Furthermore, the peptide and polymer in the composition according to this embodiment may be derived from a solid dispersion containing the peptide and polymer. In other words, the peptide and polymer in the composition according to this embodiment may be supplied from a solid dispersion containing the peptide and polymer. In other words, the peptide and polymer in the composition according to this embodiment may be those contained in a solid dispersion containing the peptide and polymer, or those released from the solid dispersion in the composition.

[0163] In the solid dispersion according to this embodiment, the substance to be dispersed is preferably uniformly dispersed in the polymer. Also, in the solid dispersion according to the present disclosure, the substance to be dispersed is preferably dispersed in the polymer in minute units, and more preferably dispersed at the molecular level.

[0164] The solid dispersion according to this embodiment refers to a semi-solid or solid substance in which multiple types of target substances (e.g., the above-mentioned peptide and polymer) are dispersed together. From the viewpoint of improving solubility, the multiple types of 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.

[0165] 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 plurality of substances are dissolved, and a method of adding a certain amount of solvent to the plurality of solid substances while mixing them. 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. Using the spray drying method, the substances in the solid dispersion can be more uniformly dispersed, thereby further improving the solubility of the substance (e.g., peptide) contained in the solid dispersion. The solvent may be any solvent that can dissolve the plurality of substances, 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.

[0166] [Other Embodiments] Another embodiment of the present invention is a composition comprising a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below, for use in combination with one or more surfactants selected from the group consisting of (I) to (III). One aspect of this embodiment is a composition that is a solid dispersion, comprising a spray-dried product of a mixture comprising a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below, for use in combination with one or more surfactants selected from the group consisting of (I) to (III). One aspect of this embodiment is a composition comprising a solid dispersion, comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, for use in combination with one or more surfactants selected from the group consisting of (I) to (III). One aspect of this embodiment is a composition comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, for use in combination with one or more surfactants selected from the group consisting of (I) to (III). and one or more polymers selected from the group consisting of (IV), (V), and (VII) below, and is to be used in combination with one or more surfactants selected from the group consisting of (I) to (III) below. In these cases, the composition to be used in combination with the surfactant may be one described above except that it does not contain a surfactant, and the surfactant to be used in combination may be one described above. The composition of this embodiment may be a solid dispersion. Alternatively, the composition of this embodiment may contain the peptide and polymer as a spray-dried mixture containing the peptide and the polymer. Preferably, the composition of this embodiment is a pharmaceutical composition. (I) anionic surfactants; (II) amphoteric surfactants; (III) nonionic surfactants; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) copovidone; (VII) polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer; (VIII) polyvinylpyrrolidone.

[0167] Another embodiment of the present invention is a composition comprising one or more surfactants selected from the group consisting of (I) to (III) below, for use in combination with a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below. In this case, the peptide, surfactant, polymer, and solid dispersion may be any of those described above. The composition according to this embodiment is preferably a pharmaceutical composition. (I) Anionic surfactant; (II) Amphoteric surfactant; (III) Nonionic surfactant; (IV) Hydroxypropylmethylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; (VI) Copovidone; (VII) Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (VIII) Polyvinylpyrrolidone

[0168] Another embodiment of the present invention is a method for improving the solubility of a peptide by combining the peptide with one or more surfactants selected from the group consisting of (I) to (III) below, and one or more polymers selected from the group consisting of (IV) to (VIII) below. One aspect of this embodiment is a method for improving the solubility of a peptide by combining a solid dispersion that is a spray-dried product of a mixture containing the peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below, with one or more surfactants selected from the group consisting of (I) to (III) below. Another aspect of this embodiment is a method for improving the solubility of a peptide by combining a solid dispersion that contains the peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, with one or more surfactants selected from the group consisting of (I) to (III) below. One aspect of this embodiment is a method for improving the solubility of a peptide by combining a solid dispersion that contains the peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, with one or more surfactants selected from the group consisting of (I) to (III) below. and one or more polymers selected from the group consisting of (IV), (V) and (VII). In these cases, the peptide, surfactant, polymer and solid dispersion may be any of those described above. (I) Anionic surfactant; (II) Amphoteric surfactant; (III) Nonionic surfactant; (IV) Hydroxypropylmethylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester and a (meth)acrylic acid ammonio alkyl ester; (VI) Copovidone; (VII) Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (VIII) Polyvinylpyrrolidone

[0169] Another embodiment of the present invention is a method for producing a composition, comprising a step of mixing a peptide, one or more surfactants selected from the group consisting of (I) to (III) below, and one or more polymers selected from the group consisting of (IV) to (VIII) below to obtain a composition (mixing step). One aspect of this embodiment is a method for producing a composition, comprising a step of combining a solid dispersion that is a spray-dried product of a mixture containing a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below with one or more surfactants selected from the group consisting of (I) to (III) below to obtain a composition (combining step). Another aspect of this embodiment is a method for producing a composition, comprising a step of combining a solid dispersion that contains a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below with one or more surfactants selected from the group consisting of (I) to (III) below to obtain a composition (combining step). One aspect of this embodiment is a method for producing a composition, comprising a step of combining a solid dispersion that contains a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below with one or more surfactants selected from the group consisting of (I) to (III) below to obtain a composition (combining step). and one or more surfactants selected from the group consisting of (I) to (III) below, and one or more polymers selected from the group consisting of (IV), (V), and (VII) below to obtain a composition (mixing step). In these cases, the peptide, surfactant, polymer, and solid dispersion may be any of those described above, and the composition produced by the production method according to this embodiment may be a composition according to one embodiment of the present invention. In these cases, combining the peptide, surfactant, and polymer includes mixing the peptide and polymer, a solid dispersion that is a spray-dried product of a mixture containing the peptide and polymer, or a solid dispersion containing the peptide and polymer with the surfactant, forming them into a single tablet, packing them into a single capsule, dissolving them in a single solvent, or otherwise allowing them to coexist by some other means. (I) anionic surfactants; (II) amphoteric surfactants; (III) nonionic surfactants; (IV) hydroxypropyl methylcellulose or a derivative thereof; (V) 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, a (meth)acrylic acid alkylamino alkyl ester, and a (meth)acrylic acid ammonio alkyl ester; and (VII) a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0170] The combining step may be carried out by a method commonly used by those skilled in the art, for example, by adding the peptide and polymer to the surfactant, or vice versa. In addition to the surfactant, peptide, and polymer, other components that may be contained in the composition may also be combined in the combining step, and examples of such other components include the above-mentioned stabilizers, preservatives, antioxidants, disintegrants, excipients, binders, glidants, lubricants, etc.

[0171] In one embodiment, the method may further include a step of forming a solid dispersion containing the peptide and the polymer (solid dispersion-forming step) prior to the combining step. Examples of the method for forming the solid dispersion in the solid dispersion-forming step include the methods described above.

[0172] The present invention is further illustrated by the following examples, but is not limited thereto. Unless otherwise specified, starting materials, starting materials, solvents, and reagents were obtained from commercial suppliers or synthesized using known methods. Hypromellose acetate succinate (hydroxypropyl methylcellulose acetate succinate, HPMCAS, hydroxypropyl methylcellulose, or one of its derivatives) used herein was obtained from Shin-Etsu Chemical Co., Ltd. (Shin-Etsu AQOAT LF). Eudragit L100, a copolymer of methyl methacrylate and methacrylic acid, was obtained from Evonik. The anionic surfactant sodium lauryl sulfate (SLS) was a product of BASF Corporation or sodium dodecyl sulfate manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. The amphoteric surfactant lauroyl-L-carnitine (LC) was obtained in the form of its hydrochloride from Sinochem Japan. Polyvinylpyrrolidone (PVP K30), copovidone (Kollidon VA64), and polyvinylcaprolactam-polyvinylacetate-polyethylene glycol graft copolymer (Soluplus) were purchased from BASF and used. The nonionic surfactant sucrose fatty acid ester (DK ester) was purchased from Daiichi Kogyo Seiyaku Co., Ltd. as DK ester SS and used. The nonionic surfactant polyoxyethylene hydrogenated castor oil 60 (HCO60) was purchased from Nikko Chemicals Co., Ltd. and used. The nonionic surfactant D-α-tocopherol polyethylene glycol 1000 succinate (Vitamin E TPGS) was purchased from Sigma-Aldrich and used. 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.

[0173] [Production Example 1] Production of Cyclic Peptides and Their Crystals The cyclic peptides CP01 to CP04 used in this example are shown in Table 1 below. These compounds were synthesized according to the method described in WO 2021 / 090855. Furthermore, although the specification refers to C-type crystals of CP02, the C-type crystals (hydrate crystals) of the peptide described in WO 2022 / 234864 were produced and used.

[0174] 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-methyl Propyl]-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]-3,9,12,15,19,2 2,25,31,34,37,45-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.

[0175] [ClogP] CP01:14.899 CP02:14.504 CP03:15.204 CP04:15.127 [Molecular weight] CP01:1478.2 CP02:1437.7 CP03:1547.7 CP04:1553.8

[0176] [Production Example 2] Production of solid dispersion (Production Example 2-1) Production of solid dispersion using HPMCAS A homogeneous suspension was prepared by adding the peptide and HPMCAS to acetone or tetrahydrofuran so that the weight ratio of the peptide to HPMCAS was 1:2 and the solid concentration was 12 wt / vol %. This suspension was spray-dried to obtain a solid dispersion.

[0177] (Production Example 2-2) Production of solid dispersion using Eudragit L100 Peptide and Eudragit L100 were added to ethanol at a weight ratio of 1:2 and a solid concentration of 8 wt / vol% to prepare a homogeneous solution. This suspension was spray-dried to obtain a solid dispersion.

[0178] [Evaluation Example] Evaluation of solubility and solid state (Evaluation Example 1-1) Powder X-ray diffraction measurements of the samples obtained in each Reference Example, Example, and Comparative Example were carried out under the following conditions: Measuring device: D8 Discover, 2D VÅNTEC-500 solid state detector (manufactured by Bruker) Radiation source: CuKα Tube voltage / current: 40 kV / 40 mA or 50 kV / 1000 μA Measurement range: 5 to 31 Exposure time: 40 to 600 seconds

[0179] (Evaluation Example 1-2) Solubility Test The solubility test for 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.

[0180] Examples, Comparative Examples, and Reference Examples Preparation and Evaluation of Pharmaceutical Compositions (Example 1, Comparative Examples 1-1, 1-2, Reference Example 1) DMSO solutions (50 μL) having the compositions shown in Table 2 were each freeze-dried to prepare powders in which the cyclic peptide CP02 was amorphous. FaSSIF (50 μL) was added to each of the resulting samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 3. In addition, the solubility difference from Reference Example 1 was calculated as an index of the solubilizing effect, and these results are also shown in Table 3. The sum of the calculated solubility differences of the Comparative Examples was compared with the solubility difference of the Examples to estimate the improvement in the solubilizing effect.

[0181] The results of Comparative Examples 1-1 and 1-2 showed that HPMCAS and SLS alone exhibited solubilizing effects of 7.2 μg / mL and 231.4 μg / mL, respectively. On the other hand, the results of Example 1 showed that the combination of SLS and HPMCAS exhibited a solubilizing effect that was 82.6 μg / mL higher than the sum of the effects when each was added alone, demonstrating a synergistic effect of approximately 1.3 times.

[0182]

[0183]

[0184] (Example 2, Comparative Examples 2-1 and 2-2, Reference Example 2) DMSO solutions (50 μL) having the compositions shown in Table 4 were freeze-dried to prepare powders in which the cyclic peptide CP03 was amorphous. FaSSIF (50 μL) was added to each of the obtained samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 5. In addition, the solubility difference from Reference Example 2 was calculated as an index of the solubilizing effect, and these results are also shown in Table 5. The sum of the calculated solubility differences of the comparative examples was compared with the solubility difference of the examples to estimate the improvement in the solubilizing effect. From the results of Comparative Example 2-1 and Comparative Example 2-2, HPMCAS and SLS alone exhibited solubilizing effects of 4.3 μg / mL and 171.6 μg / mL, respectively. On the other hand, the results of Example 2 show that the combination of SLS and HPMCAS exhibited a solubilizing effect that was 156.0 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.9 times.

[0185]

[0186]

[0187] (Example 3, Comparative Examples 3-1 and 3-2, Reference Example 3) DMSO solutions (50 μL) having the compositions shown in Table 6 were freeze-dried to prepare powders in which the cyclic peptide CP04 was amorphized. FaSSIF (50 μL) was added to each of the obtained samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 7. In addition, the solubility difference from Reference Example 3 was calculated as an index of the solubilizing effect, and these results are also shown in Table 7. The sum of the calculated solubility differences of the comparative examples was compared with the solubility difference of the examples to estimate the improvement in the solubilizing effect. From the results of Comparative Example 3-1 and Comparative Example 3-2, HPMCAS and SLS alone exhibited solubilizing effects of 3.9 μg / mL and 72.2 μg / mL, respectively. On the other hand, the results of Example 3 show that the combination of SLS and HPMCAS exhibited a solubilizing effect that was 54.7 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.7 times.

[0188]

[0189]

[0190] (Comparative Example 4, Examples 4-1 to 4-4) Solubility Measurement of CP02 Crystals HPMCAS and SLS were dissolved in FaSSIF at the concentrations shown in Table 8. These solutions were added to CP02 type C crystals and shaken overnight. Coarse particles were precipitated by centrifugation, and the supernatant was then filtered through a 0.45 μm filter, after which the solubility was measured. The results are shown in Table 9. Compared to Comparative Example 4, Examples 4-1 to 4-4 exhibited a 1.30 to 1.85 μg / mL higher solubilizing effect, confirming an approximately 1.7- to 2.1-fold improvement in solubility. These results demonstrate that the combination of HPMCAS and SLS improves the solubilizing effect even in crystalline cyclic peptides. Furthermore, when the solid residue of Example 4-4 was subjected to powder X-ray diffraction analysis, type C crystals were maintained, confirming that the improved solubility was due to the combination of HPMCAS and SLS, rather than the crystallization-inhibiting effect of HPMCAS.

[0191]

[0192]

[0193] (Reference Example 5, Examples 5-1 to 5-3, Comparative Examples 5-1 to 5-4) Measurement of Solubility of CP03 SLS was dissolved in FaSSIF to a concentration of 0.47 mg / mL to prepare a FaSSIF-SLS solution. LC was dissolved in FaSSIF to a concentration of 1.57 mg / mL to prepare a FaSSIF-LC solution. FaSSIF, FaSSIF-SLS solution, or FaSSIF-LC solution (1 mL) was added to amorphous CP03 (1 mg) or the solid dispersion (3 mg) produced under the conditions of Production Example 2-1 or 2-2, and the mixture was shaken for 2 hours. Coarse particles were precipitated by centrifugation, and the supernatant was then filtered through a 0.45 μm filter, after which the solubility was measured. The difference in solubility from Reference Example 5 was calculated as an index of the solubilizing effect. These results are shown in Table 10. The sum of the calculated solubility differences of the comparative examples was compared with the solubility differences of the examples to estimate the improvement in solubilization effect. From the results of Comparative Examples 5-1 and 5-3, HPMCAS and SLS alone exhibited solubilization effects of 19.5 μg / mL and 157.1 μg / mL, respectively. On the other hand, from the results of Example 5-1, the combination of SLS and HPMCAS exhibited a solubilization effect 117.0 μg / mL higher than the sum of the effects when each was added alone, demonstrating a synergistic effect of approximately 1.7 times.

[0194] Furthermore, the results of Comparative Example 5-2 showed that LC alone exhibited a solubilizing effect of 70.6 μg / mL. On the other hand, the results of Example 5-2 showed that the combination of LC and HPMCAS exhibited a solubilizing effect that was 113.7 μg / mL higher than the sum of the effects when each was added alone, demonstrating a synergistic effect of approximately 2.3 times.

[0195] Furthermore, the results of Comparative Example 5-4 showed that Eudragit L100 alone exhibited a solubilizing effect of 48.5 μg / mL. On the other hand, the results of Example 5-3 showed that the combination of SLS and Eudragit L100 exhibited a solubilizing effect 112.9 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.5 times.

[0196] Furthermore, when the solid residue from the solubility measurement was subjected to powder X-ray diffraction measurement, no diffraction peaks were observed under any of the conditions, and the residue was found to be amorphous. These results confirmed that the improvement in solubility due to the addition of HPMCAS or Eudragit L100 is not due to a crystallization-inhibiting effect, but rather to an increased solubilizing effect due to the combination of any one polymer selected from the group consisting of HPMCAS and Eudragit L100 with one surfactant selected from the group consisting of SLS and LC.

[0197]

[0198] (Comparative Example 6, Examples 6-1 and 6-2) Measurement of CP04 Solubility SLS was dissolved in FaSSIF to a concentration of 0.47 mg / mL to prepare a FaSSIF-SLS solution. Amorphous CP04 (1 mg) or the solid dispersion (3 mg) produced under the conditions of Production Example 2-1 or 2-2 was added to FaSSIF-SLS solution (1 mL) and shaken for 2 hours. Coarse particles were precipitated by centrifugation, and the supernatant was then filtered through a 0.45 μm filter, after which the solubility was measured. The results are shown in Table 11. SLS alone exhibited a solubilizing effect of 75.0 μg / mL. On the other hand, the combination of SLS and HPMCAS exhibited a solubilizing effect of 114.0 μg / mL, demonstrating a synergistic effect of approximately 1.5 times. Furthermore, the combination of SLS and Eudragit L100 showed a solubilizing effect of 124.2 μg / mL, demonstrating a 1.7-fold synergistic effect.

[0199] Furthermore, when the solid residue from the solubility measurement was subjected to powder X-ray diffraction measurement, no diffraction peaks were observed under any conditions, and the residue was found to be amorphous. This result confirmed that the improvement in solubility due to the addition of HPMCAS or Eudragit L100 was not due to the crystallization-inhibiting effect, but rather due to the increased solubilizing effect of HPMCAS or Eudragit L100.

[0200]

[0201] (Example 7, Comparative Examples 7-1 and 7-2, Reference Example 7) 50 μL of each DMSO solution having the composition shown in Table 12 was freeze-dried to prepare a powder in which the cyclic peptide CP01 was amorphized. 50 μL of FaSSIF was added to each of the resulting samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 13. In addition, the solubility difference from Reference Example 7 was calculated as an index of the solubilizing effect, and these results are also shown in Table 13. The sum of the calculated solubility differences of the comparative examples was compared with the solubility difference of the examples to estimate the improvement in the solubilizing effect. From the results of Comparative Example 7-1 and Comparative Example 7-2, HPMCAS and SLS alone exhibited solubilizing effects of 6.1 μg / mL and 219.1 μg / mL, respectively. On the other hand, the results of Example 7 show that the combination of SLS and HPMCAS showed a solubilizing effect that was 114.3 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.5 times.

[0202]

[0203]

[0204] (Reference Example 8, Examples 8-1 and 8-2, Comparative Examples 8-1 to 8-3) Measurement of CP01 Solubility SLS was dissolved in FaSSIF to a concentration of 0.3 mg / mL to prepare a FaSSIF-SLS solution. LC was dissolved in FaSSIF to a concentration of 0.3 mg / mL to prepare a FaSSIF-LC solution. 1 mL of FaSSIF, FaSSIF-SLS solution, or FaSSIF-LC solution was added to amorphous CP01 (1 mg) or the solid dispersion produced under the conditions of Production Example 2-1 (4.5 mg), and the mixture was shaken for 2 hours. Coarse particles were precipitated by centrifugation, and the supernatant was then filtered through a 0.45 μm filter, after which the solubility was measured. The difference in solubility from Reference Example 8 was calculated as an index of the solubilizing effect. These results are shown in Table 14. The sum of the calculated solubility differences of the comparative examples was compared with the solubility differences of the examples to estimate the improvement in solubilization effect. From the results of Comparative Examples 8-1 and 8-3, SLS and HPMCAS alone exhibited solubilization effects of 162.2 μg / mL and 40.0 μg / mL, respectively. On the other hand, from the results of Example 8-1, the combination of SLS and HPMCAS exhibited a solubilization effect 164.3 μg / mL higher than the sum of the effects when each was added alone, demonstrating a synergistic effect of approximately 1.8 times.

[0205] Furthermore, the results of Comparative Example 8-2 showed that LC alone exhibited a solubilizing effect of 41.5 μg / mL. On the other hand, the results of Example 8-2 showed that the combination of LC and HPMCAS exhibited a solubilizing effect that was 45.4 μg / mL higher than the sum of the effects when each was added alone, demonstrating a synergistic effect of approximately 1.6 times.

[0206] Furthermore, when the solid residue from the solubility measurement was subjected to powder X-ray diffraction analysis, no diffraction peaks were observed under any conditions, and the residue was found to be amorphous. This result confirmed that the improvement in solubility due to the addition of HPMCAS is not due to the crystallization-inhibiting effect, but rather to the increased solubilizing effect of the combination of HPMCAS with SLS or LC.

[0207]

[0208] (Examples 9-1 to 9-3, Comparative Examples 9-2 to 9-4, Reference Example 9) DMSO solutions (50 μL) having the compositions shown in Table 15 were each freeze-dried to prepare powders in which the cyclic peptide CP01 was amorphous. FaSSIF (50 μL) was added to each of the resulting samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 16. In addition, the solubility difference from Reference Example 9 was calculated as an index of the solubilizing effect, and these results are also shown in Table 16. The sum of the calculated solubility differences of the comparative examples was compared with the solubility difference of the examples to estimate the improvement in the solubilizing effect.

[0209] The results of Comparative Example 9-1 showed that SLS alone exhibited a solubilizing effect of 200.8 μg / mL. Furthermore, the results of Comparative Example 9-5 showed that Soluplus alone exhibited a solubilizing effect of 6.1 μg / mL. Furthermore, the results of Example 9-1 showed that the combination of SLS and Soluplus exhibited a solubilizing effect 33.1 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.2 times.

[0210] On the other hand, the results of Comparative Examples 9-2 to 9-4 show that when a solid dispersion obtained by lyophilizing a DMSO solution of a peptide and a polymer was used, PVP K30, Kollidone VA64, and Eudragit L100 did not exhibit a solubilizing effect. Furthermore, the results of Comparative Examples 9-6 to 9-8 show that when a solid dispersion obtained by lyophilizing a DMSO solution of a peptide and a polymer was used, the solubility was slightly reduced when SLS was combined with PVP K30, Kollidone VA64, or Eudragit L100 compared to the combined effect of each compound added alone, and no synergistic solubilizing effect was observed.

[0211]

[0212]

[0213] (Examples 10-1 to 10-3, Comparative Examples 10-2 to 10-4) DMSO solutions (50 μL) having the compositions shown in Table 17 were each freeze-dried to prepare powders in which the cyclic peptide CP01 was amorphized. FaSSIF (50 μL) was added to each of the resulting samples, and after shaking for 4 hours, the samples were filtered and their solubility was measured. These results are shown in Table 18. In addition, the solubility difference from Reference Example 9 was calculated as an index of the solubilizing effect, and these results are also shown in Table 18. The sum of the calculated solubility differences of the Comparative Examples was compared with the solubility difference of the Examples to estimate the improvement in the solubilizing effect.

[0214] From the results of Comparative Examples 10-1 to 10-4, HPMCAS, DKester, HCO60, and Vitamin E TPGS alone showed solubilization effects of 0.8 μg / mL, 37.3 μg / mL, 9.0 μg / mL, and 69.5 μg / mL, respectively. From the results of Example 10-1, by combining DKester and HPMCAS, compared to the sum of the effects when each was added alone, a 34.6 μg / mL higher solubilization effect was observed, and a synergistic effect of about 1.9 times was observed. From the results of Example 10-2, by combining HCO60 and HPMCAS, compared to the sum of the effects when each was added alone, a 14.4 μg / mL higher solubilization effect was observed, and a synergistic effect of about 2.5 times was observed. The results of Example 10-3 show that the combination of Vitamin E TPGS and HPMCAS exhibited a solubilizing effect that was 11.8 μg / mL higher than the combined effect of each compound added alone, demonstrating a synergistic effect of approximately 1.2 times.

[0215]

[0216]

Claims

1. A solid dispersion which is a spray-dried product of a mixture containing a peptide and one or more polymers selected from the group consisting of (IV) to (VIII) below, and one or more surfactants selected from the group consisting of (I) to (III) below, The peptide is a composition that satisfies (A) and / or (B) below: (I) Anionic surfactants; (II) Amphoteric surfactants; (III) Nonionic surfactants; (IV) Hydroxypropyl methylcellulose or its derivatives; (V) Copolymers of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, alkylaminoalkyl (meth)acrylate and ammoniaalkyl (meth)acrylate; (VI) Copovidone; (VII) Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (VIII) Polyvinylpyrrolidone; (A) The number of amino acid residues constituting the peptide is 5 or more and 30 or less; (B) The peptide contains one or more N-substituted amino acid residues.

2. A solid dispersion comprising a peptide and one or more polymers selected from the group consisting of (IV) and (VII) below, and one or more surfactants selected from the group consisting of (I) to (III) below, The peptide is a composition that satisfies (A) and / or (B) below: (I) Anionic surfactants; (II) Amphoteric surfactants; (III) Nonionic surfactants; (IV) Hydroxypropyl methylcellulose or its derivatives; (VII) Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer; (A) The number of amino acid residues constituting the peptide is 5 or more and 30 or less; (B) The peptide contains one or more N-substituted amino acid residues.

3. A composition comprising a peptide (CP02) represented by the following formula, one or more surfactants selected from the group consisting of (I) to (III) below, and one or more polymers selected from the group consisting of (IV), (V), and (VII) below: 【Chemistry 1】 (I) Anionic surfactants; (II) Amphoteric surfactants; (III) Nonionic surfactants; (IV) Hydroxypropyl methylcellulose or its derivatives; (V) Copolymers of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, alkylaminoalkyl (meth)acrylate and ammoniaalkyl (meth)acrylate; (VII) Polyvinylcaprolactam-polyvinylacetic acid-polyethylene glycol graft copolymer.

4. The composition according to any one of claims 1 to 3, wherein the surfactant is sodium lauryl sulfate.

5. The composition according to any one of claims 1 to 3, wherein the surfactant is lauroyl-L-carnitine.

6. The composition according to any one of claims 1 to 3, wherein the polymer is hydroxypropyl methylcellulose or a derivative thereof.

7. The composition according to any one of claims 1 to 3, wherein the polymer is hydroxypropyl methylcellulose acetate succinate (HPMCAS).

8. The composition according to any one of claims 1 to 3, wherein the polymer is a copolymer of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, alkylaminoalkyl (meth)acrylate and ammoniaalkyl (meth)acrylate.

9. The composition according to any one of claims 1 to 3, wherein the polymer is a copolymer of methyl methacrylate and methacrylic acid.

10. The composition according to any one of claims 1 to 3, wherein the surfactant is an anionic surfactant and the polymer is hydroxypropyl methylcellulose or a derivative thereof.

11. The composition according to any one of claims 1 to 3, wherein the surfactant is an anionic surfactant, and the polymer is a copolymer of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, alkylaminoalkyl (meth)acrylate and ammoniaalkyl (meth)acrylate.

12. The composition according to any one of claims 1 to 3, wherein the surfactant is an amphoteric surfactant and the polymer is hydroxypropyl methylcellulose or a derivative thereof.

13. The composition according to any one of claims 1 to 3, wherein the surfactant is an amphoteric surfactant, and the polymer is a copolymer of an alkyl (meth)acrylate and at least one monomer selected from the group consisting of (meth)acrylic acid, alkyl (meth)acrylate, alkylaminoalkyl (meth)acrylate and ammoniaalkyl (meth)acrylate.

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