Composition

Abstract

To provide a composition having brain migratory properties and the like. The composition of the present disclosure includes a drug, a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by formula (2), a derivative or modified form thereof, or a pharmacologically acceptable salt thereof, and at least one surfactant. Formula (2): X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34

Description

Technical Field

[0001] The present disclosure relates to a composition.

Background Art

[0002] Vasoactive intestinal peptide (VIP), a neuropeptide closely related to pituitary adenylate cyclase-activating polypeptide (PACAP), and their receptors, G protein-coupled receptors (GPCRs): VIPR1 and VIPR2 (also called VPAC1 receptor and VPAC2 receptor), are widely expressed in brain tissues and are also expressed in many peripheral tissues such as the cardiovascular system, renal system, digestive system, immune system, endocrine system, and genital system. It has been reported that overactivation of VIPR2 in brain tissues is involved in the onset of mental diseases such as schizophrenia including cognitive dysfunction (Non-Patent Document 1). Also, in breast cancer with high metastatic potential such as brain metastasis, it has been reported that activation of VIPR2 is involved in the proliferation and metastasis of breast cancer cells (Non-Patent Documents 2 and 3). In intractable colorectal cancer, it has been reported that activation of VIPR2 is involved in the proliferation of colorectal cancer cells by suppressing cancer immunity (Non-Patent Document 4).

Prior Art Documents

Non-Patent Documents

[0003]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0004] As a result of intensive research, the inventors of the present invention have found that a cyclic peptide having antagonist activity against VIPR2 and stably present in plasma can suppress cognitive function decline in mice and can suppress the growth of colorectal cancer cells. Therefore, the inventors of the present invention attempted to administer the peptide from blood and transport it to the brain tissue, but due to the blood-brain barrier (BBB) that restricts the transfer of substances from the blood to the brain tissue, there has arisen the problem that the transfer of the peptide to the brain is restricted.

[0005] Therefore, the present disclosure aims to provide a composition having brain migratory properties and the like.

Means for Solving the Problems

[0006] To achieve the above object, the composition of the present disclosure comprises a drug, a linear peptide and / or a cyclic peptide consisting of an amino acid sequence represented by the following formula (2), a derivative or a modified form thereof, or a pharmacologically acceptable salt thereof, and at least one surfactant. comprising: Formula (2): X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34 In the above formula (2), X 23 and X 24 each independently represents serine, homoserine, threonine, cysteine, D-cysteine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline. X 25represents histidine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 26 represents ornithine, lysine, homolysine, arginine, or homoarginine, X 27 represents methionine, norleucine, lysine, arginine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 28 represents methionine, leucine, norleucine, isoleucine, valine, lysine, or arginine, X 29 and X 32 each independently represents methionine, leucine, norleucine, isoleucine, valine, 2-aminoheptanoic acid, or 2-aminooctanoic acid, X 30 represents alanine, D-alanine, or 2-aminoisobutyric acid, X 31 represents glycine, alanine, asparagine, aspartic acid, glutamine, or glutamic acid, X 33 represents absent or proline, X 34 represents serine, threonine, cysteine, D-cysteine, or proline, The peptide of formula (2) has an alkyl chain directly or via a linker at the N-terminus, C-terminus, or side chain of an amino acid, X 23 or X 24 and X 34 When involved in cyclization, are cysteine or D-cysteine, and form a covalent bond between the -SH groups of their respective side chains via a disulfide bond or a linker of a methylene group, acetylmethylene group, ethylene group, or propylene group. By said formation, the peptide of formula (2) may have one cyclic structure in the molecule.

Advantages of the Invention

[0007] According to the present disclosure, it is possible to provide a composition having brain migratory properties and the like.

Brief Description of the Drawings

[0008]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Modes for Carrying Out the Invention

[0009] Hereinafter, the present disclosure will be described with examples. In the following description, the descriptions of the respective inventions are mutually applicable unless otherwise specified.

[0010] <Definition> In the present specification, "peptide" means a compound composed of unmodified amino acids (natural amino acids), modified amino acids, and / or artificial amino acids, in which two or more amino acids are condensed by peptide bonds.

[0011] In this specification, "amino acid" is used in its broadest sense and means, in addition to natural amino acids, artificial amino acids and derivatives having non-natural structures. Examples of such amino acids include L-amino acids, non-natural amino acids, and chemically synthesized compounds having properties known in the art that are characteristic of amino acids. Examples of the non-natural amino acids include α / α-disubstituted amino acids (such as α-methylated amino acids like 2-aminoisobutyric acid) whose main-chain structure is different from the natural type, N-alkyl-amino acids (such as N-methylated amino acids), D-amino acids, N-substituted glycines (peptoids), amino acids with an extended main chain (β-homoamino acids and γ-homoamino acids), amino acids whose side-chain structure is different from the natural type (such as cyclohexylalanine, allylglycine, 2-(2-pyridyl)-glycine, and 3-(1H-benzimidazole-2-yl)-alanine), amino acids with a partially substituted side chain (such as norleucine, diaminopropanoic acid, and 3-(2-pyridyl)-alanine), amino acids having an extra C, alkyl group, or methyl group in the side chain (such as homonorleucine and γ-methylleucine), amino acids having a halogen atom (F, Cl, Br, I) in the side chain (such as 3-chloro-alanine), carboxylic acids having a halogen atom (F, Cl, Br, I) in the side chain (such as 3-chloropropanoic acid), carboxylic acids having a functional group in the side chain (such as 3-butenoic acid), amino acids having an extra N or amino group in the side chain (such as β-azidoalanine and ornithine), amino acids having an extra O or methoxy group in the side chain (such as O-methyl-serine and O-methyl-threonine), amino acids having an extra hydroxy group in the side chain (such as 3-hydroxy-phenylalanine), amino acids having an extra carboxy group (-COOH) in the side chain (such as 3-carboxy-phenylalanine), amino acids having an extra S in the side chain (such as ethionine), amino acids in which the carboxylic acid functional group in the side chain is protected by an ester (such as aspartic acid-4-methyl ester), and amino acids in which the thio group (-S-) in the side chain is oxidized and converted to a sulfinyl group (-S(=O)-) and / or a sulfonyl group (-S(=O)2-) (such as methionine sulfoxide), etc.

[0012] As used herein, "pharmaceutically acceptable carrier" means a solvent and / or additive that can be commonly used in the formulation technology of pharmaceutical compositions. Preferably, the pharmaceutically acceptable carrier is substantially or completely non-toxic to the living body.

[0013] As used herein, "subject" means an animal or cells, tissues or organs derived from an animal. In particular, the "subject" is used to mean including humans. The "animal" means humans and non-human animals. Examples of the non-human animals include mammalian animals such as mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, dolphins, and seals.

[0014] As used herein, "prevention" means a decrease in the possibility of onset of a disease or pathological condition, suppression, delay or cessation of onset of a disease or pathological condition, suppression, alleviation, delay or cessation of progression of a pathological condition, or suppression, reduction, delay or cessation of exacerbation. The "prevention" may be, for example, treatment of a subject (patient) suffering from the target disease or treatment of a model animal of the target disease.

[0015] As used herein, "brain migratory" means that when the target substance is administered into the blood, the target substance passes through the blood-brain barrier, the target substance is detected in the brain tissue, a pharmacological effect related to a target protein expressed in the brain tissue is observed, and / or a downstream signal of the target protein expressed in the brain tissue changes.

[0016] As used herein, "prodrug" means a substance that is converted into a drug showing pharmacological activity by undergoing metabolism in vivo.

[0017] As used herein, "VIPR2" means vasoactive intestinal peptide receptor 2. The VIPR2 is also referred to as the VPAC2 receptor by another name. Human VIPR2 includes, for example, a protein (SEQ ID NO: 1) consisting of the amino acid sequence registered in Genbank under accession number: NP_003373.2. In addition, human VIPR2 includes, for example, a polynucleotide (SEQ ID NO: 2, including a stop codon) consisting of the nucleic acid sequence registered in Genbank under accession number: NM_003382.5.

[0018] Amino acid sequence of human VIPR2 (SEQ ID NO: 1) MRTLLPPALLTCWLLAPVNSIHPECRFHLEIQEEETKCAELLRSQTEKHKACSGVWDNITCWRPANVGETVTVPCPKVFSNFYSKAGNISKNCTSDGWSETFPDFVDACGYSDPEDESKITFYILVKAIYTLGYSVSLMSLATGSIILCLFRKLHCTRNYIHLNLFLSFILRAISVLVKDDVLYSSSGTLHCPDQPSSWVGCKLSLVFLQYCIMANFFWLLVEGLYLHTLLVAMLPPRRCFLAYLLIGWGLPTVCIGAWTAARLYLEDTGCWDTNDHSVPWWVIRIPILISIIVNFVLFISIIRILLQKLTSPDVGGNDQSQYKRLAKSTLLLIPLFGVHYMVFAVFPISISSKYQILFELCLGSFQGLVVAVLYCFLNSEVQCELKRKWRSRCPTPSASRDYRVCGSSFSRNGSEGALQFHRGSRAQSFLQTETSVI

[0019] Base sequence of human VIPR2 (SEQ ID NO: 2)

[0020] As used herein, "LRP1" means low density lipoprotein receptor-related protein 1. Human LRP1 includes, for example, a protein (SEQ ID NO: 3) consisting of the amino acid sequence registered in Genbank under accession number: Q07954. Human LRP1 also includes, for example, a polynucleotide (SEQ ID NO: 4) consisting of the nucleic acid sequence registered in Genbank under accession number: NM_002323.2.

[0021] Amino acid sequence of human LRP1 (SEQ ID NO: 3)

[0022] Base sequence of human LRP1 (including the stop codon, SEQ ID NO: 4)

[0023] In this specification, "surfactant" means a compound having a hydrophilic group and a hydrophobic group (lipophilic group). Examples of the surfactant include anionic surfactants, cationic surfactants, zwitterionic surfactants, and nonionic surfactants. The anionic surfactant means a surfactant that dissociates into anions in an aqueous solution. The cationic surfactant means a surfactant that dissociates into cations in an aqueous solution. The zwitterionic surfactant means a surfactant that dissociates into cations or anions depending on the pH of the aqueous solution in the aqueous solution. The nonionic surfactant means a surfactant that does not dissociate into ions in an aqueous solution.

[0024] Hereinafter, the present disclosure will be described with examples, but the present disclosure is not limited to the following examples and can be arbitrarily changed and implemented. In addition, each description in the present disclosure can be mutually cited unless otherwise specified. In this specification, when the expression "~" is used, it is used in the meaning including the numerical values or physical values before and after it. In this specification, the expression "A and / or B" includes "only A", "only B", and "both A and B".

[0025] <Composition> The composition of the present disclosure includes a drug, a linear peptide and / or a cyclic peptide composed of an amino acid sequence represented by the following formula (2), a derivative or a modified form thereof, or a pharmacologically acceptable salt thereof, and at least one surfactant. comprising: Formula (2): X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34 (SEQ ID NO: 5) In the formula (2), X 23and X 24 each independently represents serine, homoserine, threonine, cysteine, D-cysteine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 25 represents histidine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 26 represents ornithine, lysine, homolysine, arginine, or homoarginine, X 27 represents methionine, norleucine, lysine, arginine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 28 represents methionine, leucine, norleucine, isoleucine, valine, lysine, or arginine, X 29 and X 32 each independently represents methionine, leucine, norleucine, isoleucine, valine, 2-aminoheptanoic acid, or 2-aminooctanoic acid, X 30 represents alanine, D-alanine, or 2-aminoisobutyric acid, X 31 represents glycine, alanine, asparagine, aspartic acid, glutamine, or glutamic acid, X 33 either does not exist or represents proline, X 34 represents serine, threonine, cysteine, D-cysteine, or proline, The peptide of the formula (2) has an alkyl chain directly or via a linker at the N-terminus, C-terminus, or side chain of an amino acid, X 23 or X 24 and X 34When involved in cyclization, it is cysteine or D-cysteine, and a covalent bond is formed between the -SH groups of their respective side chains via a disulfide bond or a linker of a methylene group, an acetylmethylene group, an ethylene group, or a propylene group. By the above formation, the peptide of the formula (2) may have one cyclic structure in the molecule.

[0026] The composition of the present disclosure is characterized by including a drug, a linear peptide and / or a cyclic peptide composed of an amino acid sequence represented by the formula (2), a derivative or a modified form thereof, or a pharmaceutically acceptable salt thereof, and at least one surfactant, and other configurations and conditions are not particularly limited. Since the composition of the present disclosure has brain migration properties, it is possible to transport the drug contained in the composition of the present disclosure to the brain. Therefore, it is presumed that the composition of the present disclosure can exert its function in the central nervous system and the like.

[0027] In the present disclosure, the drug is not particularly limited as long as it is a drug for the purpose of brain migration. For example, it is preferably a peptide having antagonist activity against VIPR2. Specifically, the drug may be, for example, a cyclic peptide composed of an amino acid sequence represented by the following formula (1), a derivative or a modified form thereof, or a pharmaceutically acceptable salt thereof: Formula (1): c[X 1 -Pro 2 -X 3 -Tyr 4 -Leu 5 -Pro 6 -c(X 7 -X 8 -Leu 9 -Cys 10 -X 11 )-X 12 -X 13 (SEQ ID NO: 6) In the formula (1), X 1 represents cysteine, Mpa (3-mercaptopropionic acid) or D-cysteine, X 3represents N-methylated glycine, N-methylated alanine, 2-azetidine-2-carboxylic acid, proline, hydroxyproline, 3,4-dehydroproline, pipecolic acid, serine, or lysine, X 8 represents tyrosine, proline, or arginine, X 7 and X 11 represent any combination of lysine and aspartic acid, ornithine and glutamic acid, aspartic acid and lysine, glutamic acid and ornithine, lysine and glutamic acid, or glutamic acid and lysine, X 12 and X 13 each independently represents leucine, isoleucine, or norleucine, X 1 and Cys 10 form a disulfide bond between their respective side chains, X 7 and X 11 form an amide bond between their respective side chains, and by said formation, the peptide of the said formula (1) has two cyclic structures in the molecule, The N-terminal amino group and C-terminal carboxy group of the peptide of the said formula (1) may be modified or deleted.

[0028] When the agent is a peptide having antagonist activity against VIPR2, the function of VIPR2 is inhibited by the agent, so that improvement of cognitive function and / or suppression of the growth of cancer cells metastasized to the brain such as breast cancer are possible.

[0029] Hereinafter, each substituent in the peptide represented by the said formula (1) will be described with examples. In the description of each substituent, unless otherwise specified, the specific examples in the description of other substituents can be cited. Also, unless otherwise specified in the following description, the description of the peptide represented by the said formula (1) can be cited in the description of, for example, the salts thereof represented by the said formula (1).

[0030] As specific examples, each substituent in the said formula (1) is as follows: X 1 represents cysteine, and X 3 represents proline or serine, and X 7 represents lysine, and X 8 represents tyrosine, and X 11 represents aspartic acid, and, X 12 and X 13 each independently represents leucine, isoleucine or norleucine.

[0031] In the formula (1), the peptide may, for example, have its N-terminal amino group acetylated (Ac).

[0032] In the formula (1), the peptide may, for example, have its C-terminal carboxy group amidated (NH2).

[0033] Examples of the formula (1) include the following peptides: Ac-c[Cys 1 -Pro 2 -Pro 3 -Tyr 4 -Leu 5 -Pro 6 -c(Lys 7 -Tyr 8 -Leu 9 -Cys 10 -Asp 11 )-Leu 12 -Ile 13 -NH2(Cys 1 and Cys 10 form an S-S bond between their side chains, Lys 7 and Asp 11 form an amide bond between their side chains) (SEQ ID NO: 7)

[0034] In the above formula (1), the peptide may be composed of an amino acid sequence having identity in which 1 to several amino acids are deleted, added, inserted, and / or substituted in the amino acid sequence of the above formula (1), and may be a peptide having the activity of the peptide. The "having the activity of the peptide" means, for example, when the peptide is a VIPR2 antagonist, having antagonist activity against VIPR2. The "1 to several" means, for example, in the amino acid sequence of the above formula (1), for example, 1 to 5, 1 to 4, 1 to 3, 1 or 2, or 1. In the present disclosure, the numerical range of the number such as the number of amino acids discloses all positive integers belonging to the range. That is, for example, the description of "1 to 5" means the disclosure of all of "1, 2, 3, 4, 5" (the same applies hereinafter).

[0035] In the above formula (1), the peptide may be composed of an amino acid sequence having an identity of 80% or more with respect to the amino acid sequence of the above formula (1), and may be a peptide having the activity of the peptide. The "having the activity of the peptide" means, for example, when the peptide is a VIPR2 antagonist, having antagonist activity against VIPR2. The "identity of 80% or more" is, for example, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more with respect to the amino acid sequence of the above formula (1). The "identity" can be determined by aligning two base sequences or amino acid sequences (the same applies hereinafter). The alignment can be calculated with default parameters using, for example, BLAST, FASTA, etc.

[0036] In the present disclosure, the peptide represented by the above formula (2) is an LRP1-binding peptide. Therefore, the composition of the present disclosure can bind to LRP1 of the blood-brain barrier, and the drug contained in the composition of the present disclosure can migrate to the brain.

[0037] Hereinafter, each substituent in the peptide represented by the formula (2) will be described with examples. In the description of each substituent, unless otherwise specified, the specific examples in the description of other substituents can be cited. Further, unless otherwise specified in the following description, the description of the peptide represented by the formula (2) can be cited, for example, in the description of its salts represented by the formula (2).

[0038] As a specific example, in the formula (2), X 23 , X 24 , and X 33 are, for example, as follows: X 23 represents serine, threonine, cysteine, D-cysteine, or proline, X 24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 33 does not exist.

[0039] As a specific example, in the formula (2), X 23 , X 24 , and X 33 are, for example, as follows: X 23 represents serine, threonine, cysteine, D-cysteine, or proline, X 24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 33 represents proline.

[0040] As a specific example, in the formula (2), X 23 , X 24 , and X 33 are, for example, as follows: X23 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 24 represents serine, threonine, cysteine, D-form cysteine, or proline, X 33 represents proline.

[0041] In the formula (2), the peptide may have an alkyl chain via a linker at the N-terminus, for example. The alkyl chain may be, for example, linear or branched. The alkyl chain may constitute a part of phosphatidylethanolamine, for example.

[0042] The alkyl chain preferably has 10 to 28 carbon atoms. Specifically, the alkyl chain may be, for example, a linear structure of C10 to C28, a branched structure of (C10 to C28), 2~3 and the like. The alkyl chain may contain one or more double bonds (C=C) and / or triple bonds (C≡C), for example.

[0043] The alkyl chain may be, for example, a dimyristoyl group ((CH2) 12 CH3×2), a dipalmitoyl group ((CH2) 14 CH3×2), a distearoyl group ((CH2) 16 CH3×2), a dioleoyl group ((CH2)7C=C(CH2)7CH3×2), a dieicosanoyl group ((CH2) 18 CH3×2), a didocosanoyl group ((CH2) 20 CH3×2), a tetracosanoyl group ((CH2) 22 CH3×2), a hexacosanoyl group ((CH2) 24 CH3×2), an octacosanoyl group ((CH2) 26 CH3×2), or a triacontanoyl group ((CH2) 28Examples include CH3×2). The addition of an alkyl chain to the peptide of the formula (2) can be carried out, for example, by an addition reaction of a fatty acid to the peptide. As a specific example, the method for adding the dipalmitoyl group is, for example, as shown in FIG. 1, DBCO (Dibenzoccyclooctyne)-KS-487 described in Japanese Patent Application No. 2022-125238 (International Application PCT / JP2023 / 024137) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(6-azidohexanoyl) (16:0 azidocaproyl PE, Cat No: 870126P-25mg, manufactured by Sigma-Aldrich) are mixed and subjected to a click reaction. Examples of the method for adding the distearoyl group include, for example, as shown in FIG. 2, reacting DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-PEG13-NHS (Cat No: BP-28871, manufactured by BROADPHARM), DSPE-PEG-NHS, MW600 (Cat No: BP-26254, manufactured by BROADPHARM), or DSPE-PEG-NHS, MW1000 (Cat No: BP-26220, manufactured by BROADPHARM) with the α-amino group at the N-terminus of the peptide or the ε-amino group of the side chain of lysine arranged on the N-terminal side. Note that the MW600 and the MW1000 represent the average molecular weight of the PEG chain. PEGX (X is a number) means -(CH2CH2O)X-. Further, examples of the method for adding the distearoyl group include, for example, as shown in FIG. 3, reacting DSPE-NHS (Cat No: BP-26160, manufactured by BROADPHARM) with the α-amino group at the N-terminus of the peptide or the ε-amino group of the side chain of lysine arranged on the N-terminal side without using a linker. Examples of the method for adding the dioleoyl group include, for example, a method of crosslinking 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine and a peptide with a crosslinking agent such as DSS (Disuccinimidyl suberate).

[0044] In the formula (2), the linker may contain, for example, PEG. When the linker contains PEG, the average molecular weight of the PEG is preferably, for example, 2000 or less, specifically preferably 1000 or less, 600 or less. The PEG may be, for example, a single substance without a distribution in the degree of polymerization or a mixture with a distribution.

[0045] In the formula (2), the linker may be represented by, for example, X N . The X N is, for example, any 1 to 22 amino acid residues. The X N is not particularly limited as long as it is a sequence that does not inhibit the binding to LRP1, and examples include alternative sequences of PEG linkers such as glycine linkers and GS linkers combining glycine and serine. Specifically, Lys-(Gly) 1~19 -Thr-Pro (SEQ ID NO: 8), Lys-(Gly-Gly-Gly-Ser)5-Pro (SEQ ID NO: 9), Lys-(Gly-Gly-Gly-Gly-Ser)4-Pro (SEQ ID NO: 10), (Gly) 1~20 -Thr-Pro (SEQ ID NO: 11), (Gly-Gly-Gly-Ser)5-Pro (SEQ ID NO: 12), (Gly-Gly-Gly-Gly-Ser)4-Pro (SEQ ID NO: 13), etc.

[0046] Examples of the formula (2) include the following peptides. c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (S-S bond is formed between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 14)

[0047] The formula (2) includes, for example, the following peptides. Gly 1 -Thr 2 -Pro 3 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 15)

[0048] The formula (2) includes, for example, the following peptides. (C15)2-DBCO-PEG5-DBCO-PEG4-Gly 1 -Thr 2 -Pro 3 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 15)

[0049] The formula (2) includes, for example, the following peptides. Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Thr 7 -Pro 8 -c(Cys 23 -Thr 24 -Tyr25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 16)

[0050] The formula (2) includes, for example, the following peptides. (C17)2-PEG(MW600)-Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Thr 7 -Pro 8 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 16)

[0051] The formula (2) includes, for example, the following peptides. Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Gly 7 -Thr 8 -Pro 9 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 17)

[0052] The above formula (2) includes, for example, the following peptides. (C17)2-PEG(MW600)-Gly 1 -Gly 2 -Gly 3 -Gly 4 -Gly 5 -Gly 6 -Gly 7 -Thr 8 -Pro 9 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 form an S-S bond between side chains) (SEQ ID NO: 17)

[0053] The above formula (2) includes, for example, the following peptides. (Gly-Gly-Gly-Ser)5-Pro 21 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys34 Form an S-S bond between side chains) (SEQ ID NO: 18)

[0054] The formula (2) includes, for example, the following peptides. (C17)2-(Gly-Gly-Gly-Ser)5-Pro 21 -c(Cys 23 -Thr 24 -Tyr 25 -Lys 26 -Tyr 27 -Nle 28 -Leu 29 -Ala 30 -Glu 31 -Nle 32 -Cys 34 )-OH (Cys 23 and Cys 34 Form an S-S bond between side chains) (SEQ ID NO: 18)

[0055] In the formula (2), the peptide may consist of an amino acid sequence having identity with the amino acid sequence of the formula (2) in which 1 to several amino acids are deleted, added, inserted, and / or substituted, and may be a peptide having the activity of the peptide. The "having the activity of the peptide" means, for example, that the peptide has LRP1 binding activity. The "1 to several" means, for example, 1 to 5, 1 to 4, 1 to 3, 1 or 2, or 1 in the amino acid sequence of the formula (2).

[0056] In the formula (2), the peptide may consist of an amino acid sequence having 80% or more identity with the amino acid sequence of the formula (2), and may be a peptide having the activity of the peptide. The "having the activity of the peptide" means, for example, having LRP1 binding activity. The "80% or more identity" means, for example, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, 99% or more with respect to the amino acid sequence of the formula (1).

[0057] In the present disclosure, the peptide of the formula (1) or formula (2) may be, for example, its derivative. The derivative may be, for example, one in which the saturated fatty chain of the peptide is replaced by an unsaturated fatty chain, one in which some of the atoms of the peptide are replaced by other atoms containing radioactive or non-radioactive isotope atoms, one in which the amide bond of the peptide is replaced by a thioamide bond (-NH-C(=S)-), one in which the amide bond of the peptide is replaced by an alkene (-C=C-), one in which the amide bond of the peptide is replaced by an alkyl (-C-C-), one in which the amide bond of the peptide is replaced by hydroxyethylene (-C(-OH)-C-), one in which the amide bond of the peptide is replaced by an ester (-O-C(=O)-), one in which the amide bond of the peptide is replaced by an alkene (-C=C-), one in which the amide bond of the peptide is replaced by (-C-NH-), or one in which the amide bond of the peptide is replaced by (-C(=O)-C-), and the like.

[0058] In the present disclosure, the peptide of the formula (1) or formula (2) may be, for example, a modified form thereof. The modified form includes, for example, those in which the α-carbon of the peptide is disubstituted, those in which the amide bond of the peptide is N-alkylated, those in which a part of the functional group of the peptide is modified by halogenation, cyanation, nitration, oxidation, hydroxylation, amination, deamination, dehydrogenation, amidation, acetylation, methoxylation, prenylation, alkylation, etc. (for example, those in which a part of the amino group of the peptide is acetylated, formylated, myristoylated, palmitoylated, pyroglutaminated, alkylated or deaminated, those in which a part of the carboxy group of the peptide is N-pyrrolidinylated or N-piperidinylated, those which are amides (amide, methylamide, ethylamide, p-nitroanilide, β-naphthylamide, etc.) or esters (methyl ester, ethyl ester, thioester, etc.), etc.), those in which the S of the peptide is sulfoxide S(=O) or sulfone S(=O)2, those in which the peptide is multimerized via a chemical linker, those in which the peptide is biotinylated, those in which the peptide is fluorescently labeled, those in which the peptide is luminescently labeled, and further those in which the peptide is fused with an alkyl chain, polyethylene glycol, antibody, lectins, sugar chain, enzyme, membrane-permeable peptide, low molecular compound, or a molecule that induces ubiquitination of a protein, etc.

[0059] In the present disclosure, the peptide of the formula (1) or formula (2) may be, for example, a salt thereof. The salt is not limited as long as it is a salt with a physiologically acceptable base or acid, and examples include addition salts of inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts of organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acid, succinic acid, citric acid, benzoic acid, acetic acid, etc.), inorganic bases (ammonium hydroxide, or an alkali or alkaline earth metal hydroxide, carbonate, bicarbonate, etc.), addition salts of amino acids, etc.

[0060] In the present disclosure, the peptide of the formula (1) or formula (2) may be, for example, a prodrug. The prodrug is, for example, a compound in which the amino group of the peptide is acylated, alkylated or phosphorylated (for example, a compound in which the amino group of the peptide is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated), a compound in which the hydroxy group of the peptide is acylated, alkylated, phosphorylated, or borylated (for example, a compound in which the hydroxy group of the peptide is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated), a compound in which the hydroxy group and carboxy group of the peptide are esterified or amidated (for example, a compound in which the hydroxy group and carboxy group of the peptide are C 1-6 alkyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methyl amidated). These compounds can be produced, for example, from the peptide of the formula (1) or formula (2) by known methods.

[0061] The prodrug may be, for example, one that changes to the peptide under physiological conditions. In this case, the change to the peptide under physiological conditions can be referred to, for example, the description on pages 163 to 198 of "Drug Development", Volume 7, Molecular Design, published by Hirokawa Shoten in 1990.

[0062] In the present disclosure, the prodrug may, for example, form a salt. Examples of the salt include the salts exemplified as the salts of the peptide.

[0063] In the present disclosure, the peptide may be, for example, a crystal. When the peptide is a crystal, for example, the crystal form may be single or a mixture. The crystal can be produced, for example, by known crystallization methods.

[0064] In the present disclosure, the peptide may be, for example, a pharmaceutically acceptable cocrystal or a cocrystal salt. The crystal or the cocrystal salt is a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (such as structure, melting point, heat of fusion, hygroscopicity, solubility, and stability, etc.). The cocrystal or the cocrystal salt can be produced, for example, by known cocrystallization methods.

[0065] In the present disclosure, the surfactant is not particularly limited as long as it has, for example, the effect of solubilizing the peptide of the drug. The surfactant is, for example, polyoxyethylene castor oil, polyoxyethylene sorbitan fatty acid ester, Triton (trademark) X-100, nonoxynol-9, triethanolamine, triethanolamine polypeptide oleate, polyoxyethylene-660 hydroxystearate (PEG-15, Solutol H15), soybean lecithin, poloxamer, hexadecylamine, octadecylamine, octadecyl amino acid ester, lysophosphatidylcholine, dimethyldioctadecylammonium bromide, methoxyhexadecyl glycerol, pluronic (registered trademark) polyol, polyamine (such as pyran, dextran sulfate, poly IC, carbopol), oil emulsion, and mineral gel (such as aluminum phosphate), etc. The surfactant is preferably polyoxyethylene castor oil (including derivatives) such as polyoxyethylene-35-ricinoleate, and polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan fatty acid ester. The surfactant may be a synthetic product or a commercially available product. The surfactant may be used, for example, alone or in combination of multiple types.

[0066] When using commercially available polyoxyethylene castor oil, examples include CREMOPHOR® EL, CREMOPHOR® ELP, CREMOPHOR® RH 40, etc. from BASF.

[0067] When using commercially available polyoxyethylene sorbitan fatty acid esters, examples include TWEEN® 80 (polysorbate 80), sorbitan monooleate polyoxyethylene 20, TWEEN® 85 (polysorbate 85), TWEEN® 20 (polysorbate 20), etc. from ICI Americas.

[0068] The content of the surfactant is preferably, for example, 1% by mass to 30% by mass, 3% by mass to 20% by mass, 5% to 15% by mass, or 10% by mass to 20% by mass based on the total mass of the composition.

[0069] The composition of the present disclosure may further contain, for example, dimethyl sulfoxide (DMSO). The DMSO is known as an organic solvent with relatively low toxicity for dissolving poorly soluble substances. When the composition of the present disclosure contains the DMSO, the content of DMSO in the composition of the present disclosure is preferably 50% by mass or less, more preferably 20% by mass or less, based on the total mass of the composition. The content of DMSO in the composition of the present disclosure is, for example, 0.1% by mass or more, 1% by mass or more, or 5% by mass or more based on the total mass of the composition.

[0070] The composition of the present disclosure may contain, for example, micelles. The micelles are preferably composed of, for example, a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by the formula (2), its derivative or modified form, or a pharmaceutically acceptable salt thereof, and the surfactant. The micelles preferably contain, for example, the drug.

[0071] The compositions of the present disclosure are, for example, liquid or solid. Examples of the solvent for the liquid include water, an aqueous solvent of an aqueous / organic mixture, etc. Examples of the pH of the liquid include pH 5.5 to 7.5, pH 6 to 7, pH 6 to 6.5. In the case of the liquid, it may be stored at room temperature, refrigerated (for example, 2 to 8°C) or frozen (for example, -20°C or -80°C). When the composition of the present disclosure is solid, the solid can be prepared by a suitable method, for example, in the form of a cake or powder by adding a cryoprotectant. When the composition of the present disclosure is in the form of an individual, since it can be dissolved, it can be reconstituted with a suitable medium to prepare a liquid suitable for administration. Suitable solvents for reconstituting the solid include, for example, water, physiological saline, buffer solution, phosphate buffered saline, Ringer's (lactate added or dextrose) solution, essential inorganic medium, alcohol / aqueous solution, dextrose solution, etc.

[0072] The compositions of the present disclosure may further contain a pharmaceutically acceptable carrier. Examples of the carrier include, for example, a suspending agent, solubilizing agent, stabilizer, isotonic agent, preservative, anti-adsorption agent, surfactant, diluent, medium, pH adjuster, soothing agent, buffer, sulfur-containing reducing agent, antioxidant, etc. for administering the active ingredient, and can be appropriately added within a range that does not interfere with the effects of the present disclosure.

[0073] The suspending agent is not particularly limited, and examples thereof include methylcellulose, polysorbate 80, hydroxyethylcellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate, etc.

[0074] The solubilizing agent is not particularly limited, and examples thereof include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate, macrogol, ethyl ester of castor oil fatty acid, etc.

[0075] The stabilizer is not particularly limited, and examples thereof include dextran 40, methylcellulose, gelatin, sodium sulfite, sodium metabisulfite, etc.

[0076] The isotonic agent is not particularly limited, and examples thereof include D-mannitol, sorbitol, and the like.

[0077] The preservative is not particularly limited, and examples thereof include methyl paraben, ethyl paraben, sorbic acid, phenol, cresol, chlorocresol, and the like.

[0078] The anti-adsorption agent is not particularly limited, and examples thereof include human serum albumin, lecithin, dextran, ethylene oxide-propylene oxide copolymer, hydroxypropyl cellulose, methyl cellulose, hydrogenated castor oil, polyethylene glycol, and the like.

[0079] The sulfur-containing reducing agent is not particularly limited, and examples thereof include those having a sulfhydryl group such as N-acetylcysteine, N-acetylhomocysteine, thioxoctic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and its salts, sodium thiosulfate, glutathione, thioalkanoic acids having 1 to 7 carbon atoms, and the like.

[0080] The antioxidant is not particularly limited, and examples thereof include erythorbic acid, dibutylhydroxytoluene, butylhydroxyanisole, α-tocopherol, tocopherol acetate, L-ascorbic acid and its salts, L-ascorbic acid palmitate, L-ascorbic acid stearate, sodium bisulfite, sodium sulfite, triamyl gallate, propyl gallate or sodium ethylenediaminetetraacetate (EDTA), sodium pyrophosphate, sodium metaphosphate, and other chelating agents.

[0081] The composition of the present disclosure may further appropriately contain commonly added components such as inorganic salts such as sodium chloride, potassium chloride, calcium chloride, sodium phosphate, potassium phosphate, sodium hydrogen carbonate; organic salts such as sodium citrate, potassium citrate, sodium acetate; saccharides such as glucose; and the like.

[0082] In the composition of the present disclosure, in view of the properties of being easily metabolized and excreted, the peptide can be subjected to various modifications. Examples of the modifications include the addition of an alkyl chain, polyethylene glycol, a sugar chain, or the like. By the modification, the blood retention time of the composition of the present disclosure can be prolonged and the antigenicity can be reduced.

[0083] In the composition of the present disclosure, the peptide of the present disclosure may be encapsulated. The encapsulation can be carried out, for example, by using a biodegradable polymer compound such as polylactic acid-glycolic acid (PLGA), porous hydroxyapatite, liposome, surface-modified liposome, an emulsion prepared with an unsaturated fatty acid, nanoparticles, nanospheres, or the like as a sustained-release base.

[0084] The composition of the present disclosure can be used, for example, in vitro and can also be used in vivo The composition of the present disclosure can be used, for example, as a research reagent or as a pharmaceutical. In the former case, the composition of the present disclosure can also be, for example, a test reagent or a test kit.

[0085] The administration target of the composition of the present disclosure is not particularly limited. When the composition of the present disclosure is in vivo used, the target (administration target) can, for example, refer to the aforementioned examples. When the composition of the present disclosure is in vitro used, the administration target includes, for example, cells, tissues, organs, etc. The cells include, for example, cells collected from a living body, cultured cells, etc. The tissues or organs include, for example, tissues (biological tissues) or organs collected from a living body.

[0086] When the composition of the present disclosure is in vivoWhen used, the subject to be administered may be a healthy subject who does not suffer from a central nervous system disease and / or brain metastatic cancer, or a subject who may be suffering from a central nervous system disease and / or brain metastatic cancer, or a patient suffering from a central nervous system disease and / or brain metastatic cancer. The subject to be administered is preferably a subject for whom prevention and / or treatment of a central nervous system disease and / or brain metastatic cancer is desired.

[0087] Examples of the central nervous system diseases include mental disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, etc.), pediatric mental disorders (attention deficit disorder, attention deficit / hyperactivity disorder, conduct disorder, autism, etc.), neurodegenerative disorders, neural stem cell disorders, neural progenitor disorders, ischemic disorders, traumatic nerve disorders, mood disorders, psychomotor disorders, sleep disorders (hypersomnia, circadian rhythm sleep disorder, insomnia, abnormal sleep behavior, sleep apnea, etc.), mental disorders such as anxiety (acute stress disorder, generalized anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, obsessive-compulsive disorder, etc.), factitious mental disorders (acute hallucinatory mania, etc.), impulse control disorders (compulsive gambling, intermittent explosive disorder, etc.), mood disorders (bipolar type I disorder, bipolar type II disorder, mania, mixed mood state, etc.), major depressive disorder, chronic depression, seasonal depression, psychotic depression, seasonal depression, cognitive disorders (amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, Lewy body dementia, vascular dementia, drug-related dementia, tardive dyskinesia, metabolic myoclonus, dystonia, delirium, Pick's disease, Creutzfeldt-Jakob disease, HIV disease, Gilles de la Tourette syndrome, epilepsy, muscle spasm, mild cognitive impairment, etc.), mental retardation (spasticity, Down syndrome, fragile X syndrome, etc.); premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), postpartum depression, neuron injury disorders (eye injury, retinal disease or macular degeneration of the eye, tinnitus, hearing impairment, cerebral edema, etc.), Parkinson's disease, Parkinson's disease-like disorder, migraine, epilepsy, Alzheimer's disease, brain injury, stroke, cerebrovascular diseases (cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cerebral hypoxia-ischemia, etc.), drug dependence (narcotic dependence, alcoholism, amphetamine dependence, cocaine addiction, nicotine dependence, drug withdrawal syndrome, etc.), eating disorders (anorexia nervosa, bulimia nervosa, binge eating disorder, polyphagia, obesity, compulsive eating disorder, pica, etc.).

[0088] The usage conditions (administration conditions) of the composition of the present disclosure are not particularly limited. For example, depending on the type of the active ingredient in the composition, the type of the administration subject, etc., the administration form, administration timing, dosage, etc. can be appropriately set.

[0089] Examples of the administration method of the composition of the present disclosure include intrathecal administration, intramuscular administration, subcutaneous administration, intravenous administration, etc. Transdermal administration is exemplified. However, for example, regardless of the technique of the administrator, it can be administered safely and stably. Therefore, it is preferable to administer intramuscularly or subcutaneously by injection or infusion. Examples of the transdermal administration include iontophoresis method.

[0090] The dosage of the composition of the present disclosure is an amount that can transport the drug contained in the composition of the present disclosure to the brain with respect to the administration subject, that is, an effective dosage. The dosage can be appropriately determined depending on, for example, the age, body weight, symptoms, etc. of the administration subject.

[0091] The number of administrations of the composition of the present disclosure is one or more times. The plurality of times is, for example, 2 times, 3 times, 4 times, 5 times or more. The number of administrations may be appropriately determined while confirming the effect on the administration subject. When administering multiple times, the administration interval can be appropriately determined while confirming the preventive effect on the administration subject, and examples thereof include once a day, once a week, once every two weeks, once a month, once every three months, once every six months, etc.

[0092] The composition of the present disclosure can prevent or alleviate at least one symptom caused by a central nervous system disease and / or brain metastatic cancer in a subject to be administered. Symptoms of suffering from a central nervous system disease and / or brain metastatic cancer include headache, vomiting, visual impairment, disturbance of consciousness, convulsive seizures, paralysis, and speech disorder, etc. The composition of the present disclosure can prevent or alleviate at least one symptom associated with suffering from a central nervous system disease and / or brain metastatic cancer. The alleviation of the above symptoms can be evaluated subjectively or objectively. Specific examples include self-evaluation by the subject to be administered; evaluation by a doctor; QOL (Quality of Life) evaluation; evaluation of delaying the progression of symptoms of suffering from a central nervous system disease and / or brain metastatic cancer, or alleviating the severity of symptoms of suffering from a central nervous system disease and / or brain metastatic cancer, etc. The above objective evaluation can be an evaluation by an animal or an evaluation by a human.

[0093] The examination of the brain metastatic cancer can be performed, for example, using a Computed Tomography (CT) examination, a Positron Emission Tomography (PET) examination, or a Magnetic Resonance Imaging (MRI) examination, etc.

[0094] The primary cancer of the brain metastatic cancer includes, for example, lung cancer, breast cancer, melanoma, renal cell carcinoma, kidney cancer, colorectal cancer, gastric cancer, head and neck cancer, hepatocellular carcinoma, liver cancer, ovarian cancer, prostate cancer, bladder cancer, pancreatic cancer, endometrial cancer, thyroid cancer, malignant lymphoma, and sarcoma, etc.

[0095] The manufacturing method of the composition of the present disclosure can refer to, for example, the method described in Example 1 below. As an example, the manufacturing method of the composition of the present disclosure can be manufactured by mixing the drug, the peptide represented by the formula (2), and the surfactant.

[0096] The mixing temperature is not particularly limited as long as, for example, the drug, the peptide represented by the formula (2), and the surfactant can be mixed. As an example, 40 to 60 °C is preferable. The mixing time is not particularly limited as long as, for example, the peptide represented by the formula (2) and the surfactant can be mixed. As an example, about 60 minutes to 6 hours is preferable.

[0097] Before the mixing, the molecule containing the alkyl chain may be dissolved in DMSO, and after the dissolution, the peptide represented by the formula (2) may be added to alkylate the peptide represented by the formula (2).

[0098] <Composition for use in improving cognitive function> In another aspect, the present disclosure provides a composition capable of improving cognitive function. The composition for use in improving the cognitive function of the present disclosure includes the composition of the present disclosure. According to the composition for use in improving the cognitive function of the present disclosure, an effect of improving cognitive function can be obtained.

[0099] The "improvement of cognitive function" means that at least one of the functions of learning, memory, attention, and processing is improved. The improvement of the cognitive function can be evaluated, for example, by performing a measurement of the cognitive function. The measurement of the cognitive function can be evaluated, for example, by a learning test, a memory test, and / or an attention / processing speed test. Examples of the learning test include a passive avoidance test, a fear conditioning test, etc. Examples of the memory test include a Y-maze task, an 8-arm radial maze task, a novel object recognition test, a Morris water maze test, etc. Examples of the attention / processing speed test include a 5-choice serial reaction time task, etc. The measurement of the cognitive function is preferably evaluated by a novel object recognition test according to Example 1(7) described below.

[0100] The composition for use in improving cognitive function of the present disclosure can, for example, improve cognitive function by being used on an administration subject. Thereby, the composition for use in improving cognitive function of the present disclosure can, for example, obtain an effect of improving cognitive function. The usage conditions (administration conditions) of the composition for use in improving cognitive function of the present disclosure can refer to the description of the usage conditions of the composition of the present disclosure.

[0101] <Composition for use in suppressing the growth of tumors in the brain> In another aspect, the present disclosure provides a composition capable of suppressing the growth of tumors in the brain. The composition for use in suppressing the growth of tumors in the brain of the present disclosure includes the composition of the present disclosure. According to the composition for use in suppressing the growth of tumors in the brain of the present disclosure, an effect of suppressing the growth of tumors in the brain can be obtained.

[0102] The suppression of the growth of tumors in the brain can be evaluated, for example, by performing a CT examination, a PET examination, an MRI examination, etc. and measuring the size of the tumor.

[0103] The composition for use in suppressing the growth of tumors in the brain of the present disclosure can, for example, suppress the growth of tumors in the brain by being used on an administration subject. Thereby, the composition for use in suppressing the growth of tumors in the brain of the present disclosure can, for example, obtain an effect of suppressing the growth of tumors in the brain. The usage conditions (administration conditions) of the composition for use in suppressing the growth of tumors in the brain of the present disclosure can refer to the description of the usage conditions of the composition of the present disclosure.

[0104] <Use> In another aspect, the present disclosure is the use of the composition of the present disclosure for use in preventing and / or treating central nervous system diseases and / or brain metastatic cancer. Further, the present disclosure is the use of the composition of the present disclosure for use in improving cognitive function and / or suppressing the growth of tumors in the brain. The use of the composition of the present disclosure can refer to the description of the composition of the present disclosure.

Examples

[0105] Next, examples of the present invention will be described. However, the present invention is not limited by the following examples. Commercially available reagents were used based on their protocols unless otherwise indicated. Note that "mol / l" may also be denoted as "M".

[0106] [Example 1] It was confirmed that the composition of the present disclosure exhibits brain migratory properties.

[0107] (1) Materials Ac-c[Cys-Pro-Pro-Tyr-Leu-Pro-c(Lys-Tyr-Leu-Cys]-Asp)-Leu-Ile-NH2 (KS-133, SEQ ID NO: 7) and DBCO-PEG5-DBCO-PEG4-Gly-Thr-Pro-c(Cys-Thr-Tyr-Lys-Tyr-Nle-Leu-Ala-Glu-Nle-Cys)-OH (DBCO-KS-487, SEQ ID NO: 15) were each synthesized by commissioning Scrum Co., Ltd. (Tokyo, Japan) according to the methods described in Patent Document 1 and Patent Document 2. Also, 16:0 azidocaproyl PE (Cat No: 870126P-25mg) was purchased from Sigma-Aldrich, Cremophor EL (Cat No: 09727-14) was purchased from Nacalai Tesque, Inc., and ICG (Cat No: I0535) was purchased from Tokyo Chemical Industry Co., Ltd.

[0108] (2) Preparation of a composition containing ICG, dipalmitoylated KS-487, and Cremophor EL As shown in Figure 1, 3.0 mg of DBCO-KS-487 (molecular weight 2701.2 g / mol) and 1.0 mg of 16:0 azidocaproyl PE (molecular weight 848.2 g / mol) were dissolved in DMSO (100 μl). After the dissolution, the mixture was allowed to stand at room temperature (about 25 °C, the same hereinafter) overnight, and dipalmitoylated KS-487 was prepared by a click reaction between the DBCO group and the azido group.

[0109] As shown in Fig. 4, micelles were prepared using ICG, dipalmitoylated KS-487, and Cremophor EL. Specifically, 1.0 mg of ICG was added to a DMSO solution containing dipalmitoylated KS-487 and dissolved. Next, 100 μl of Cremophor EL and 350 μl of purified water were mixed to prepare a surfactant solution. After the preparation, the surfactant solution was added to the DMSO solution containing dipalmitoylated KS-487 and ICG. The sample after the addition was thoroughly mixed by vortexing and sonicated in hot water at about 50 °C. After the sonication, 450 μl of purified water was added. The sample after the addition was thoroughly mixed by vortexing and sonicated again in hot water at about 50 °C. The sample after the sonication was cooled on ice, mixed by vortexing about once every 30 minutes, sonicated in cold water, and cooled on ice, which was repeated. By carrying out this step for 3 to 4 hours, a clear composition (Composition D) was obtained. The composition was stored refrigerated until use.

[0110] (3) Preparation of Composition Containing ICG ICG was dissolved in DMSO to prepare Composition A containing ICG and not containing KS-487 and Cremophor EL.

[0111] (4) Preparation of Composition Containing ICG and Cremophor EL Composition B was prepared by the same method as described in Example 1(2) except that dipalmitoylated KS-487 was not added.

[0112] (5) Preparation of Composition Containing ICG, Dipalmitoylated KS-487, and Cremophor EL Composition C was prepared by the same method as described in Example 1(2) except that dipalmitoylated KS-487 was added at 0.3 times based on the addition amount of dipalmitoylated KS-487 (1-fold) in the composition of Example 1(2).

[0113] The final concentration of Cremophor EL in the prepared Compositions B to D was 10% by volume, and the final concentration of DMSO was 10% by volume.

[0114] (6) Evaluation of brain migration by bioimaging For the compositions of the present disclosure, evaluation of brain migration was performed by bioimaging. Specifically, Compositions A to D prepared in the above Examples 1(2) to (5) were diluted 10-fold with PBS (final concentration of ICG: 0.1 mg / ml). After the dilution, 400 μl of the diluted solution of each composition was administered subcutaneously to BALB / cCrSlc mice (6 weeks old, n = 3). 48 hours after the administration, perfusion was performed with PBS, and the brain was collected. Then, bioimaging was performed using VISQUETM InVivo Smart-LF (manufactured by VIEWWORKS). In the bioimaging, the excitation wavelength was measured at 740 - 790 nm, and the fluorescence wavelength was measured at 810 - 860 nm. Image analysis was performed using CleVueTM Software (VIEWWORKS). These results are shown in FIG. 5.

[0115] FIG. 5 is a bioimaging image and graph showing the brain migration of Compositions A to D. In FIG. 5(A), from left to right, a bright field, the front side of the brain in fluorescence observation, the back side of the brain in fluorescence observation, and a split section of the brain in fluorescence observation are shown. In FIG. 5(B), the vertical axis represents the fluorescence intensity, and the horizontal axis represents the type of composition. As shown in FIG. 5, when Composition A consisting only of ICG was administered, fluorescence derived from ICG was hardly detected in the brain. For Composition B that does not contain dipalmitoylated KS-487, fluorescence derived from ICG was slightly detected in the brain. For Compositions C and D containing dipalmitoylated KS-487, fluorescence derived from ICG was detected in the brain in a concentration-dependent manner with respect to the added concentration of dipalmitoylated KS-487. From these results, it was found that the composition containing ICG, dipalmitoylated KS-487, and Cremophor EL migrates to the brain tissue by administration to the peripheral tissue.

[0116] (7) Novel object recognition test It has been reported that when the VIPR2 antagonist peptide KS-133 is administered intranasally to mice, the phosphorylation of CREB, which is one of the downstream signals of VIPR2 in the brain tissue, is significantly suppressed (Reference 1). In addition, it has been reported that when KS-133 is administered subcutaneously to neonatal mice with immature blood-brain barriers in a schizophrenia model at an early stage of postnatal development, the decline in cognitive function is suppressed (Reference 1). These findings indicate that when KS-133 reaches the brain tissue of schizophrenia model mice, the cognitive function changes. Therefore, it was examined whether the cognitive function changes when a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL is administered to schizophrenia model mice. Specifically, a composition (Composition E) containing KS-133, dipalmitoylated KS-487, and Cremophor EL was prepared. The preparation was carried out in the same manner as in Example 1(2), except that KS-133 was used instead of ICG. The schizophrenia model mice were prepared by the method described in Japanese Patent Application No. 2020-059721 (International Publication No. 2021 / 202059). A VIPR2-selective agonist, Ro25-1553, was administered subcutaneously to 1-day-old mice once a day for 14 days. After the subcutaneous administration, the composition E or physiological saline was administered subcutaneously to the grown mice (6 weeks old) continuously raised once a day for 14 days. For the subcutaneous administration, a dilution with physiological saline was used so that the KS-133 contained in the composition E was 3 mg / kg. Twenty-four hours after the subcutaneous administration, object recognition training was performed. Also, 24 hours after the subcutaneous administration, the mice were subjected to a recognition test for novel objects. The recognition test for novel objects was conducted during the light period (8:00 - 20:00) according to Non-Patent Document 1. First, the test mice were acclimated for 10 minutes a day for 3 consecutive days in an acrylic-modified polyvinyl chloride test cage (30 cm × 30 cm × 35 cm) lined only with a sterilized wooden soft tip (Sankyo Labo Service Co., Ltd.) in a soundproof laboratory set at an illuminance of 30 lux.On the fourth day of the test, two different objects (randomly selected two from a golf ball, a Lego block, a plastic cylinder, and a power outlet) were placed at a position 8 cm away from the wall, and the mice were allowed to explore freely for 10 minutes (training trial). Twenty-four hours after the exploration, the mice were allowed to explore freely for 5 minutes in a test cage where object b was replaced with object c, a novel object (test trial). The behaviors of the mice in the training trial and the test trial were video-recorded, and the exploratory time for each of the two objects was measured. The ratio (%) of the difference in the exploratory time between object c and object a to the total exploratory time in the test trial was calculated as the discrimination index. These results are shown in Fig. 6. Reference 1: Sakamoto, Kotaro et al. “Generation of KS-133 as a Novel Bicyclic Peptide with a Potent and Selective VIPR2 Antagonist Activity that Counteracts Cognitive Decline in a Mouse Model of Psychiatric Disorders.” Frontiers in pharmacology vol. 12 751587. 4 Nov. 2021, doi:10.3389 / fphar.2021.751587

[0117] Figure 6 is a graph showing the results of the test trials. In Figure 6(A), the vertical axis represents the exploratory time, and the horizontal axis represents the breakdown of the administered drug. In Figure 6(B), the vertical axis represents the discrimination index. As shown in Figure 6(A), in the group administered with the composition E (n = 16 / group), the exploratory time for the novel object was significantly longer than that for the known object (p-value by Student's t-test was less than 0.05). On the other hand, in the control group administered with physiological saline (n = 16 / group), no significant difference in the exploratory time was observed. Also, as shown in Figure 6(B), the discrimination index of the group administered with the composition E was significantly higher compared to the control group administered with physiological saline (p-value by Student's t-test was less than 0.001). From these results, it was found that when a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL is administered to peripheral tissues, it migrates to the brain tissue and improves cognitive function.

[0118] (8) Evaluation of the amount of KS-133 migrating to the brain tissue by pharmacokinetic study A drug solution was prepared by diluting a composition E containing KS-133, dipalmitoylated KS-487, and Cremophor EL with physiological saline so that the concentration of KS-133 was 2 mg / mL. After the preparation, the drug solution was administered subcutaneously to male ICR mice at 10 mg / kg. At 1, 3, 6, and 10 hours after the administration, plasma, liver, cerebral cortex, and hypothalamus were collected, and the concentration of KS-133 in each tissue was measured by LC-MS / MS. These results are shown in Figure 7.

[0119] Figure 7 is a table showing the results of the pharmacokinetic test. As shown in Figure 7, the concentration of KS-133 in plasma (nmol / ml) was "14.717, 22.465, 10.600, 2.005 at 1, 3, 6, and 10 hours, respectively" or "19.112, 24.938, 13.369, 1.008 at 1, 3, 6, and 10 hours, respectively". The peak concentration of KS-133 in plasma was 3 hours after administration. The concentration of KS-133 in the hypothalamus (nmol / g) was "0.074, 0.124, 0.027, 0.015 at 1, 3, 6, and 10 hours, respectively" or "0.097, 0.137, 0.065, 0.015 at 1, 3, 6, and 10 hours, respectively". The peak concentration of KS-133 in the hypothalamus was 3 hours after administration. The concentration of KS-133 in the cerebral cortex (nmol / g) was "0.096, 0.121, 0.056, 0.014 at 1, 3, 6, and 10 hours, respectively" or "0.105, 0.137, 0.068, 0.011 at 1, 3, 6, and 10 hours, respectively". The peak concentration of KS-133 in the cerebral cortex was 3 hours after administration. And the concentration of KS-133 in the liver (nmol / g) was "3.642, 6.308, 3.796, 0.941 at 1, 3, 6, and 10 hours, respectively" or "4.750, 8.292, 3.883, 0.612 at 1, 3, 6, and 10 hours, respectively". The peak concentration of KS-133 in the liver was 3 hours after administration. The change in the concentration of KS-133 in any tissue was well correlated. From the results of this pharmacokinetic test, it was shown that KS-133 migrated into brain tissues such as the hypothalamus and cerebral cortex in a time-dependent manner by the administration of the composition E. And these results strongly support that the mechanism of the medicinal effect shown by the composition of the present disclosure containing KS-133, dipalmitoylated KS-487, and Cremophor EL in Figure 6 is the result of KS-133 migrating from peripheral tissues to brain tissues and suppressing the downstream signal of VIPR2.

[0120] As described above, the present disclosure has been described with reference to the embodiments and examples, but the present disclosure is not limited to the above embodiments and examples. Various changes that can be understood by those skilled in the art can be made to the configuration and details of the present disclosure within the scope of the present disclosure.

[0121] This application claims priority based on Japanese Patent Application No. 2023-223187 filed on December 28, 2023, and incorporates the entire disclosure thereof herein.

[0122] Patents, patent applications, and documents cited in this specification are incorporated by reference herein as if their contents were specifically described herein.

[0123] <Supplementary Note> Some or all of the above embodiments and examples may be described as follows, but are not limited thereto. <Composition> (Supplementary Note 1) A drug, A linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by the following formula (2), a derivative or modified form thereof, or a pharmaceutically acceptable salt thereof, At least one surfactant, A composition comprising: Formula (2): X 23 -X 24 -X 25 -X 26 -X 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -X 34 In the formula (2), X 23 and X 24 each independently represents serine, homoserine, threonine, cysteine, D-cysteine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 25represents histidine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 26 represents ornithine, lysine, homolysine, arginine, or homoarginine, X 27 represents methionine, norleucine, lysine, arginine, tyrosine, O-methyl-tyrosine, phenylalanine, 4-amino-phenylalanine, 4-fluoro-phenylalanine, or 4-chloro-phenylalanine, X 28 represents methionine, leucine, norleucine, isoleucine, valine, lysine, or arginine, X 29 and X 32 each independently represents methionine, leucine, norleucine, isoleucine, valine, 2-aminoheptanoic acid, or 2-aminooctanoic acid, X 30 represents alanine, D-alanine, or 2-aminoisobutyric acid, X 31 represents glycine, alanine, asparagine, aspartic acid, glutamine, or glutamic acid, X 33 represents absent or proline, X 34 represents serine, threonine, cysteine, D-cysteine, or proline, The peptide of formula (2) has an alkyl chain directly or via a linker at the N-terminus, C-terminus, or side chain of the amino acid, X 23 or X 24 and X 34 When involved in cyclization, are cysteine or D-cysteine, and form a covalent bond between the -SH groups of their respective side chains via a disulfide bond or a linker of a methylene group, acetylmethylene group, ethylene group, or propylene group, and by said formation, the peptide of formula (2) may have one cyclic structure in the molecule. (Appendix 2) In the formula (2), X 23 represents serine, threonine, cysteine, D-cysteine, or proline, X 24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 33 is the composition described in Appendix 1 that does not exist. (Appendix 3) In the formula (2), X 23 represents serine, threonine, cysteine, D-cysteine, or proline, X 24 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 33 represents proline, the composition described in Appendix 1. (Appendix 4) In the formula (2), X 23 represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutyric acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline, X 24 represents serine, threonine, cysteine, D-cysteine, or proline, X 33 represents proline, the composition described in Appendix 1. (Appendix 5) The agent is a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), its derivative or modified form, or a pharmacologically acceptable salt thereof, the composition according to any one of Appendices 1 to 4: Formula (1): c[X 1 -Pro2 -X 3 -Tyr 4 -Leu 5 -Pro 6 -c(X 7 -X 8 -Leu 9 -Cys 10 -X 11 )-X 12 -X 13 In the above formula (1), X 1 represents cysteine, Mpa (3-mercaptopropionic acid) or D-cysteine, X 3 represents N-methylated glycine, N-methylated alanine, 2-azetidine-2-carboxylic acid, proline, hydroxyproline, 3,4-dehydroproline, pipecolic acid, serine, or lysine, X 8 represents tyrosine, proline, or arginine, X 7 and X 11 represent any combination of lysine and aspartic acid, ornithine and glutamic acid, aspartic acid and lysine, glutamic acid and ornithine, lysine and glutamic acid, or glutamic acid and lysine, X 12 and X 13 each independently represent leucine, isoleucine, or norleucine, X 1 and Cys 10 form a disulfide bond between their respective side chains, X 7 and X 11 form an amide bond between their respective side chains, and by this formation, the peptide of the above formula (1) has two cyclic structures in the molecule, The N-terminal amino group and C-terminal carboxy group of the peptide of the above formula (1) may be modified or deleted. (Appendix 6) In the above formula (2), The alkyl chain has 10 or more carbon atoms, and the composition according to any one of Appendices 1 to 5. (Supplementary Note 7) In the formula (2), the alkyl chain is a dimyristoyl group ((CH2) 12 CH3×2), a dipalmitoyl group ((CH2) 14 CH3×2), a distearoyl group ((CH2) 16 CH3×2), a dioleoyl group ((CH2)7C=C(CH2)7CH3×2), a docosanoyl group ((CH2) 18 CH3×2), a tetracosanoyl group ((CH2) 20 CH3×2), a hexacosanoyl group ((CH2) 22 CH3×2), an octacosanoyl group ((CH2) 24 CH3×2), or a triacontanoyl group ((CH2) 26 CH3×2), and is the composition according to any one of Supplementary Notes 1 to 6. 28 CH3×2), and is the composition according to any one of Supplementary Notes 1 to 6. (Supplementary Note 8) The peptide of (2) has an alkyl chain via a linker at the N-terminus, and is the composition according to any one of Supplementary Notes 1 to 7. (Supplementary Note 9) In the formula (2), the linker contains PEG, and the average molecular weight of the PEG is 2000 or less, and is the composition according to any one of Supplementary Notes 1 to 8. (Supplementary Note 10) The linker is represented by X N and X N is any amino acid residue of 1 to 22, and is the composition according to any one of Supplementary Notes 1 to 9. (Supplementary Note 11) X N is Lys-(Gly) 1~19 -Thr-Pro, Lys-(Gly-Gly-Gly-Ser)5-Pro, Lys-(Gly-Gly-Gly-Gly-Ser)4-Pro, (Gly) 1~20 -Thr-Pro, (Gly-Gly-Gly-Ser)5-Pro, or (Gly-Gly-Gly-Gly-Ser)4-Pro, and is the composition according to Supplementary Note 10. (Supplementary Note 12) The composition according to any one of Supplementary Notes 1 to 11, wherein the content of the surfactant is 10% by mass or more based on the total mass of the composition. (Supplementary Note 13) The composition according to any one of Supplementary Notes 1 to 12, wherein the surfactant is selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid ester. (Supplementary Note 14) The composition according to Supplementary Note 13, wherein the surfactant is polyoxyethylene-35-ricinoleate or polysorbate 80. (Supplementary Note 15) The composition according to any one of Supplementary Notes 1 to 14, further comprising dimethyl sulfoxide. (Supplementary Note 16) Comprising micelles, The micelles are composed of a linear peptide and / or cyclic peptide consisting of the amino acid sequence represented by the formula (2), a derivative or modified form thereof, or a pharmaceutically acceptable salt thereof, and the surfactant. The composition according to any one of Supplementary Notes 1 to 15, wherein the micelles contain the drug. (Supplementary Note 17) The composition according to any one of Supplementary Notes 1 to 16, for use in the prevention and / or treatment of central nervous system diseases and / or brain metastatic cancer. (Supplementary Note 18) The composition according to any one of Supplementary Notes 1 to 17, having brain metastatic properties. (Supplementary Note 19) The composition according to any one of Supplementary Notes 1 to 18, for use in improving cognitive function. [Industrial Applicability]

[0124] As described above, according to the present disclosure, a composition having brain metastatic properties can be provided. Therefore, the present disclosure can be said to be extremely useful, for example, in the field of pharmaceuticals.

Claims

1. An agent, a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by the following formula (2), or a pharmacologically acceptable salt thereof, at least one surfactant, and a composition comprising: Formula (2): Gly 1 - Thr 2 - Pro 3 - c(Cys 23 - Thr 24 - Tyr 25 - Lys 26 - Tyr 27 - Nle 28 - Leu 29 - Ala 30 - Glu 31 - Nle 32 - Cys 34 ) - OH (forming an S - S bond between the side chains of Cys 23 and Cys 34 ) (SEQ ID NO: 15) The peptide of formula (2) has an alkyl chain directly or via a linker at the N - terminus, C - terminus, or side chain of an amino acid, and the alkyl chain has 10 or more carbon atoms.

2. The composition according to claim 1, wherein the agent is a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), or a pharmacologically acceptable salt thereof: Formula (1): Ac - c[Cys 1 - Pro 2 - Pro 3 - Tyr 4 - Leu 5 - Pro 6 - c(Lys 7 - Tyr 8 - Leu 9 - Cys 10 ] - Asp 11 ) - Leu 12 - Ile 13 - NH 2 (forming an S - S bond between the side chains of Cys 1 and Cys 10 and forming an amide bond between the side chains of Lys 7 and Asp 11 ) (SEQ ID NO: 7).

3. In the formula (2), The alkyl chain is a dimyristoyl group ((CH ２ ) １２ CH ３ × 2), dipalmitoyl group ((CH ２ ) １４ CH ３ × 2), distearoyl group ((CH ２ ) １６ CH ３ × 2), dioleoyl group ((CH ２ ) ７ C=C(CH ２ ) ７ CH ３ × 2), dieicosanoyl group ((CH ２ ) １８ CH ３ × 2), didocosanoyl group ((CH ２ ) ２０ CH ３ × 2), tetracosanoyl group ((CH ２ ) ２２ CH ３ × 2), hexacosanoyl group ((CH ２ ) ２４ CH ３ × 2), octacosanoyl group ((CH ２ ) ２６ CH ３ × 2), or triacontanoyl group ((CH ２ ) ２８ CH ３ 3. The composition according to claim 1 or 2, wherein

4. The composition according to claim 1 or 2, wherein the peptide of (2) has an alkyl chain via a linker at the N - terminus.

5. In the formula (2), the linker contains PEG, and the average molecular weight of the PEG is 2000 or less, the composition according to claim 1 or 2.

6. The linker is X Ｎ represented by X Ｎ The composition according to claim 1 or 2, wherein X is any of 1 to 22 amino acid residues.

7. X Ｎ is Lys-(Gly) １～１９ -Thr-Pro, Lys-(Gly-Gly-Gly-Ser) ５ -Pro, Lys-(Gly-Gly-Gly-Gly-Ser) ４ -Pro, (Gly) １～２０ -Thr-Pro, (Gly-Gly-Gly-Ser) ５ -Pro, or (Gly-Gly-Gly-Gly-Ser) ４ -Pro, the composition according to claim 6

8. The composition according to claim 1 or 2, wherein the content of the surfactant is 10% by mass or more based on the total mass of the composition.

9. The composition according to claim 1 or 2, wherein the surfactant is selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid esters.

10. The composition according to claim 9, wherein the surfactant is polyoxyethylene - 35 - ricinoleate or polysorbate 80.

11. Furthermore, the composition according to claim 1 or 2, which contains dimethyl sulfoxide.

12. containing micelles, The micelle is composed of a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by the formula (2), or a pharmacologically acceptable salt thereof, and the surfactant. The micelle is the composition according to claim 1 or 2, which contains the drug.

13. The composition according to claim 1 or 2, for use in the prevention and / or treatment of central nervous system diseases and / or brain metastatic cancer.

14. The composition according to claim 1 or 2, which has brain migratory property.

15. The composition according to claim 1 or 2, for use in improving cognitive function.

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