Composition

Abstract

Provided is, inter alia, a composition having brain migration properties.　A composition according to the present disclosure contains: a drug; a linear peptide and / or a cyclic peptide composed of an amino acid sequence represented by formula (2), a derivative or modification thereof, or a pharmacologically acceptable salt thereof; and at least one surfactant. Formula (2): X23-X24-X25-X26-X27-X28-X29-X30-X31-X32-X33-X34

Description

composition

[0001] The present disclosure relates to compositions.

[0002] Vasoactive intestinal peptide (VIP), a neuropeptide closely related to pituitary adenylate cyclase-activating polypeptide (PACAP), and its receptors, G protein-coupled receptors (GPCRs): VIPR1 and VIPR2 (also called VPAC1 receptor and VPAC2 receptor), are widely expressed in brain tissue and also in numerous peripheral tissues, including the cardiovascular, renal, gastrointestinal, immune, endocrine, and reproductive systems. It has been reported that excessive activation of VIPR2 in brain tissue is involved in the development of psychiatric disorders, including schizophrenia, including cognitive impairment (Non-Patent Document 1). It has also been reported that activation of VIPR2 is involved in the proliferation and metastasis of breast cancer cells, including those with high metastatic potential, such as brain metastasis (Non-Patent Documents 2 and 3). It has also been reported that activation of VIPR2 is involved in the proliferation of colon cancer cells, which is intractable, by suppressing cancer immunity (Non-Patent Document 4).

[0003] Ago, Yukio et al. “Reductions in synaptic proteins and selective alteration of prepulse inhibition in male C57BL / 6 mice after postnatal administration of a VIP receptor (VIPR2) agonist.” Psychopharmacology vol. 232,12 (2015): 2181-9. doi:10.1007 / s00213-014-3848-zAsano, Satoshi et al. “Vasoactive intestinal peptide-VIPR2 signaling regulates tumor cell migration.” Frontiers in oncology vol. 12 852358. 27 Sep. 2022, doi:10.3389 / fonc.2022.852358Asano, Satoshi et al. “Vasoactive intestinal peptide receptor 2 signaling promotes breast cancer cell proliferation by enhancing the ERK pathway.” Peptides vol. 161 (2023): 170940. doi:10.1016 / j.peptides.2023.170940Kittikulsuth, Wararat et al. “Vasoactive intestinal peptide blockade suppresses tumor growth by regulating macrophage polarization and function in CT26 tumor-bearing mice.” Scientific reports vol. 13,1 927. 17 Jan. 2023, doi:10.1038 / s41598-023-28073-6

[0004] As a result of extensive research, the present inventors have found that a cyclic peptide that has antagonist activity against VIPR2 and is stable in plasma can suppress cognitive decline in mice and the proliferation of colon cancer cells. Therefore, the present inventors attempted to administer the peptide from the blood or the like to transport it to brain tissue, but encountered the problem that the blood-brain barrier (BBB), which restricts the transfer of substances from the blood to brain tissue, restricted the transfer of the peptide to the brain.

[0005] Therefore, an object of the present disclosure is to provide a composition and the like that is brain-localizable.

[0006] In order 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 modification 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 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-diaminobutanoic 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 ２７represents 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 either absent or proline; X ３４ represents serine, threonine, cysteine, D-cysteine, or proline, the peptide of formula (2) has an alkyl chain at the N-terminus, C-terminus, or side chain of an amino acid directly or via a linker, and X ２３ or X ２４ and X ３４ is cysteine ​​or D-cysteine ​​when involved in cyclization, and forms a covalent bond between the respective -SH groups in the side chains via a disulfide bond or a linker such as a methylene group, an acetylmethylene group, an ethylene group, or a propylene group, and the peptide of formula (2) may have one cyclic structure in the molecule by the formation of a disulfide bond or a covalent bond between the respective -SH groups in the side chains.

[0007] According to the present disclosure, it is possible to provide compositions and the like that are brain-localizing.

[0008] FIG. 1 is a scheme showing a method for adding a dipalmitoyl group. FIG. 2 is a scheme showing a method for adding a distearoyl group. FIG. 3 is a scheme showing a method for adding a distearoyl group. FIG. 4 is a scheme showing a method for preparing a composition of the present disclosure. FIG. 5 is a bioimaging image and graph showing the brain penetration of compositions A to D. FIG. 6 is a graph showing the results of a test trial. FIG. 7 is a table showing the results of a pharmacokinetic study.

[0009] The present disclosure will be described below with reference to examples. In the following description, the descriptions of the inventions can be mutually incorporated unless otherwise specified.

[0010] <Definitions> As used herein, "peptide" refers to a compound composed of unmodified amino acids (natural amino acids), modified amino acids, and / or artificial amino acids, and formed by condensing two or more amino acids via peptide bonds.

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

[0012] As used herein, the term "pharmaceutically acceptable carrier" refers to a solvent and / or additive that can be commonly used in the formulation of pharmaceutical compositions. The pharmaceutically acceptable carrier is preferably, for example, one that is almost or completely non-toxic to living organisms.

[0013] As used herein, the term "subject" refers to an animal or a cell, tissue, or organ derived from an animal. The term "subject" particularly includes humans. The term "animal" refers to humans and non-human animals. Examples of non-human animals include mammals such as mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys, dolphins, and sea lions.

[0014] As used herein, "prevention" means reducing the possibility of onset of a disease or pathological condition, suppressing, delaying, or stopping the onset of a disease or pathological condition, suppressing, alleviating, delaying, or stopping the progression of a pathological condition, or suppressing, reducing, delaying, or stopping the worsening of the condition. The "prevention" may be, for example, treatment of a subject (patient) who develops the target disease, or treatment of an animal model of the target disease.

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

[0016] As used herein, the term "prodrug" refers to a substance that is converted into a drug that exhibits pharmacological activity by undergoing metabolism in the living body.

[0017] As used herein, "VIPR2" refers to vasoactive intestinal peptide receptor 2. VIPR2 is also known as VPAC2 receptor. Examples of human VIPR2 include a protein (SEQ ID NO: 1) consisting of the amino acid sequence registered in Genbank under accession number NP_003373.2. Examples of human VIPR2 include 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) MRTLLPPALLTCWLLAPVNSIHPECRFHLEIQEEETKCAELLRSQTEKHKACSGVWDNITCWRPANVGETVTVPCPKVFSNFYSKAAGNISKNCTSDGWSETFPDFVDAC GYSDPEDESKITFYILVKAIYTLGYSVSLMSLATGSIILCLFRKLHCTRNYIHLNLFLSFILRAISVLVKDDVLYSSSGTLHCPDQPSSWVGCKLSLVFLQYCIMANFFW LLVEGLYLHTLLVAMLPPRRCFLAYLLIGWGLPTVCIGAWTAARLYLEDTGCWDTNDHSVPWWVIRIPILISIIVNFVLFISIIRILLQKLTSPDVGGNDQSQYKRLAK STLLLIPLFGVHYMVFAVFPISISSKYQILFELCLGSFQGLVVAVLYCFLNSEVQCELKRKWRSRCPTPSASRDYRVCGSSFSRNGSEGALQFHRGSRAQSFLQTETSVI

[0019]

[0020] As used herein, "LRP1" refers to low density lipoprotein receptor-related proteins 1. Examples of human LRP1 include a protein (SEQ ID NO: 3) consisting of the amino acid sequence registered in Genbank under accession number Q07954. Examples of human LRP1 include a polynucleotide (SEQ ID NO: 4) consisting of the nucleic acid sequence registered in Genbank under accession number NM_002323.2.

[0021]

[0022]

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

[0024] The present disclosure will be described below using examples, but the present disclosure is not limited to the following examples and can be implemented with any modifications. Furthermore, the descriptions in this disclosure can be mutually incorporated unless otherwise specified. In this specification, when the expression "~" is used, it is used to mean including the numerical or physical values ​​before and after it. In addition, in this specification, the expression "A and / or B" includes "A only," "B only," and "both A and B."

[0025] <Composition> 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 modification 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 (SEQ ID NO: 5) In the formula (2), X ２３ and X ２４each independently represents serine, homoserine, threonine, cysteine, D-cysteine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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 represents either absent or proline; X ３４ represents serine, threonine, cysteine, D-cysteine, or proline, the peptide of formula (2) has an alkyl chain at the N-terminus, C-terminus, or side chain of an amino acid directly or via a linker, and X ２３ or X ２４ and X ３４ is cysteine ​​or D-cysteine ​​when involved in cyclization, and forms a covalent bond between the respective -SH groups in the side chains via a disulfide bond or a linker such as a methylene group, an acetylmethylene group, an ethylene group, or a propylene group, and the peptide of formula (2) may have one cyclic structure in the molecule by the formation of a disulfide bond or a covalent bond between the respective -SH groups in the side chains.

[0026] The composition of the present disclosure is characterized by comprising a drug, a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by formula (2), a derivative or modification thereof, or a pharmacologically acceptable salt thereof, and at least one surfactant, and other components and conditions are not particularly limited. The composition of the present disclosure has brain-transporting properties, and is therefore capable of transporting a 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, etc.

[0027] In the present disclosure, the drug is not particularly limited as long as it is a drug intended for brain delivery, and is preferably, for example, a peptide having antagonist activity against VIPR2. Specifically, the drug may be, for example, a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), a derivative or modified form thereof, or a pharmacologically 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 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 １１represents 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 forms a disulfide bond between each side chain, and X ７ and X １１ form an amide bond between the respective side chains, and as a result of this formation, the peptide of formula (1) has two cyclic structures in the molecule, and the N-terminal amino group and the C-terminal carboxyl group of the peptide of formula (1) may be modified or deleted.

[0028] When the drug is a peptide having antagonist activity against VIPR2, the drug inhibits the function of VIPR2, thereby making it possible to improve cognitive function and / or inhibit the proliferation of cancer cells that have metastasized to the brain, such as breast cancer cells.

[0029] Hereinafter, examples of each substituent in the peptide represented by formula (1) will be described. Unless otherwise specified in the description of each substituent, specific examples in the description of other substituents can be used. Furthermore, unless otherwise specified in the following description, the description of the peptide represented by formula (1) can be used to describe, for example, the salts thereof represented by formula (1).

[0030] As a specific example, each substituent in the 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 have, for example, an acetylated (Ac) N-terminal amino group.

[0032] In the formula (1), the peptide may be, for example, a peptide in which the C-terminal carboxyl group is amidated (NH ２ ) may also be used.

[0033] The formula (1) includes, for example, the following peptide: 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 (Cys １ and Cys １０ Forms an S-S bond between the side chains of Lys ７ and Asp １１ (SEQ ID NO: 7)

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

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

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

[0037] Hereinafter, examples of each substituent in the peptide represented by formula (2) will be described. In the description of each substituent, unless otherwise specified, specific examples in the description of other substituents can be used. Furthermore, unless otherwise specified in the following description, the description of the peptide represented by formula (2) can be used to describe, for example, the salts thereof represented by formula (2).

[0038] As a specific example, in the formula (2), X ２３ , X ２４ , and X ３３ is, for example: X ２３ represents serine, threonine, cysteine, D-cysteine, or proline; X ２４ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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 is, for example: X ２３ represents serine, threonine, cysteine, D-cysteine, or proline; X ２４ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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 is, for example: X ２３ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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.

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

[0042] The number of carbon atoms in the alkyl chain is preferably C10 to C28. Specifically, the alkyl chain may have, for example, a linear structure of C10 to C28, (C10 to C28) ２～３ The alkyl chain may include, for example, one or more double bonds (C=C) and / or triple bonds (C≡C).

[0043] The alkyl chain may be, for example, 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 ３2×2) and the like. The addition of an alkyl chain to the peptide of formula (2) can be carried out, for example, by an addition reaction of a fatty acid to the peptide. Specific examples of the method for adding the dipalmitoyl group include, as shown in FIG. 1 , a method in which DBCO (Dibenzocyclooctyne)-KS-487 described in Japanese Patent Application No. 2022-125238 (International Application No. PCT / JP2023 / 024137) and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(6-azidohexanoyl) (16:0 azidocaproyl PE, Cat No: 870126P-25 mg, Sigma-Aldrich) are mixed and subjected to a click reaction. Examples of methods for adding the distearoyl group include reacting the N-terminal α-amino group of a peptide or the side chain ε-amino group of a lysine located on the N-terminal side with DSPE (1,2-distearoyl-sn-glycero-3-phosphoethanolamine)-PEG-NHS (Cat. No. BP-28871, BroadPharma), DSPE-PEG-NHS, MW600 (Cat. No. BP-26254, BroadPharma), or DSPE-PEG-NHS, MW1000 (Cat. No. BP-26220, BroadPharma), as shown in Figure 2. Note that MW600 and MW1000 represent the average molecular weight of the PEG chain. PEGX (X is a number) refers to -(CHCHO)X-. Examples of methods for adding the distearoyl group include reacting DSPE-NHS (Cat No: BP-26160, manufactured by Broadpharm) without a linker with the N-terminal α-amino group of the peptide or the side chain ε-amino group of a lysine located on the N-terminal side, as shown in Figure 3. Examples of methods for adding the dioleoyl group include 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 include, for example, PEG. When the linker includes PEG, the average molecular weight of the PEG is, for example, preferably 2000 or less, specifically, preferably 1000 or less, more preferably 600 or less. The PEG may be, for example, a single substance with no distribution in degree of polymerization, or a mixture with a distribution.

[0045] In the formula (2), the linker may be, for example, X Ｎ The X may be represented by the following formula: Ｎ is, for example, any amino acid residue of 1 to 22. Ｎ is not particularly limited as long as it does not inhibit binding to LRP1, and examples thereof include sequences that can replace PEG linkers, such as a glycine linker and a GS linker that combines 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) and the like.

[0046] The formula (2) includes, for example, the following peptide: 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 S—S bond formed between side chains) (SEQ ID NO: 14)

[0047] Examples of the formula (2) include the following peptides: 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 S—S bond formed between side chains) (SEQ ID NO: 15)

[0048] Examples of the formula (2) include 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 S—S bond formed between side chains) (SEQ ID NO: 15)

[0049] Examples of the formula (2) include the following peptides: 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 S—S bond formed between side chains) (SEQ ID NO: 16)

[0050] Examples of the formula (2) include the following peptide: (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 S—S bond formed between side chains) (SEQ ID NO: 16)

[0051] Examples of the formula (2) include the following peptides: 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 -Nle３２ -Cys ３４ ) -OH (Cys ２３ and Cys ３４ S—S bond formed between side chains) (SEQ ID NO: 17)

[0052] Examples of the formula (2) include the following peptide: (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 S—S bond formed between side chains) (SEQ ID NO: 17)

[0053] The formula (2) includes, for example, the following peptide: (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 S—S bond formed between side chains) (SEQ ID NO: 18)

[0054] Examples of the formula (2) include the following peptide: (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 S—S bond formed between side chains) (SEQ ID NO: 18)

[0055] In the formula (2), the peptide may be, for example, a peptide having the activity of the peptide, which consists of an amino acid sequence having the same identity as the amino acid sequence of the formula (2) in which one to several amino acids are deleted, added, inserted, and / or substituted. The term "having the activity of a peptide" means, for example, that the peptide has LRP1 binding activity. The term "one 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 be, for example, a peptide consisting of an amino acid sequence having 80% or more identity to the amino acid sequence of the formula (2) and having the activity of the peptide. The term "having peptide activity" means, for example, having LRP1 binding activity. The "80% or more identity" is, for example, 80% or more, 85% or more, 90% or more, 95% or more, 96% or more, 97% or more, 98% or more, or 99% or more with respect to the amino acid sequence of the formula (1).

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

[0058] In the present disclosure, the peptide of formula (1) or (2) may be, for example, a modified form thereof. The modified form includes, for example, a peptide in which the α-carbon of the peptide is disubstituted, a peptide in which the amide bond of the peptide is N-alkylated, a peptide in which some of the functional groups of the peptide are modified by halogenation, cyanation, nitration, oxo-, hydroxylation, ammination, deamination, dehydrogenation, amidation, acetylation, methoxylation, prenylation, alkylation, or the like (for example, a peptide in which some of the amino groups of the peptide are acetylated, formylated, myristoylated, palmitoylated, pyroglutamated, alkylated, or deaminated, a peptide in which some of the carboxy groups of the peptide are N-pyrrolidinylated or N-piperidinylated, an amide (amide, methylamide, ethylamide, p-nitroanilide, β-naphthylamide, etc.) or an ester (methyl ester, ethyl ester, thioester, etc.), or a peptide in which S of the peptide is sulfoxide S(═O) or sulfone S(═O). ２Examples of such peptides include those in which the peptide is a polymerized peptide via a chemical linker, a peptide labeled with biotin, a peptide labeled with fluorescence, a peptide labeled with luminescence, and a peptide fused with an alkyl chain, polyethylene glycol, an antibody, a lectin, a sugar chain, an enzyme, a membrane-permeable peptide, a low molecular weight compound, or a molecule that induces protein ubiquitination.

[0059] In the present disclosure, the peptide of formula (1) or (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 thereof include addition salts with inorganic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, etc.), addition salts with organic acids (p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carboxylic acids, succinic acid, citric acid, benzoic acid, acetic acid, etc.), addition salts with inorganic bases (ammonium hydroxide, alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, etc.), and addition salts of amino acids.

[0060] In the present disclosure, the peptide of formula (1) or (2) may be, for example, a prodrug. The prodrug may be, 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 borated (for example, a compound in which the hydroxy group of the peptide is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated), or a compound in which the hydroxy group or carboxy group of the peptide is esterified or amidated (for example, a compound in which the hydroxy group or carboxy group of the peptide is C １－６Examples include 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 methylamidated compounds. These compounds can be produced, for example, from the peptide of formula (1) or formula (2) by known methods.

[0061] The prodrug may be, for example, one that is converted into the peptide under physiological conditions. In this case, the conversion into the peptide under physiological conditions can be described, for example, in "Drug Development," Vol. 7, Molecular Design, pp. 163-198, Hirokawa Shoten, 1990.

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

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

[0064] In the present disclosure, the peptide may be, for example, a pharmaceutically acceptable co-crystal or co-crystal salt. The crystal or the co-crystal salt is a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, stability, etc.). The co-crystal or the co-crystal salt can be prepared, for example, by known co-crystallization methods.

[0065] In the present disclosure, the surfactant is not particularly limited as long as it has the effect of solubilizing the peptide of the drug. Examples of the surfactant include 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, lysolecithin, dimethyl-dioctadecylammonium bromide, methoxyhexadecylglycerol, Pluronic (registered trademark) polyol, polyamine (e.g., pyran, dextran sulfate, poly IC, carbopol), oil emulsion, and mineral gel (e.g., aluminum phosphate). The surfactant is preferably a polyoxyethylene castor oil (including derivatives) such as polyoxyethylene-35-ricinoleate, or a polyoxyethylene sorbitan fatty acid ester such as polyoxyethylene sorbitan fatty acid ester. The surfactant may be a synthetic product or a commercially available product. For example, one type of surfactant may be used, or multiple types may be used in combination.

[0066] When a commercially available product of the polyoxyethylene castor oil is used, examples thereof include CREMOPHOR (registered trademark) EL, CREMOPHOR (registered trademark) ELP, and CREMOPHOR (registered trademark) RH 40 manufactured by BASF.

[0067] When a commercially available product of the polyoxyethylene sorbitan fatty acid ester is used, examples thereof include TWEEN (registered trademark) 80 (polysorbate 80), polyoxyethylene 20 sorbitan monooleate, TWEEN (registered trademark) 85 (polysorbate 85), and TWEEN (registered trademark) 20 (polysorbate 20), all of which are available 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% by mass 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). DMSO is known as a relatively non-toxic organic solvent for dissolving poorly soluble substances. When the composition of the present disclosure contains DMSO, the content of DMSO in the composition of the present disclosure is, for example, 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 include, for example, a micelle. The micelle is preferably composed of, for example, a linear peptide and / or a cyclic peptide consisting of an amino acid sequence represented by formula (2), a derivative or modification thereof, or a pharmacologically acceptable salt thereof, and the surfactant. The micelle preferably contains, for example, the drug.

[0071] The composition of the present disclosure may be, for example, a liquid or solid. Examples of the liquid solvent include water and aqueous solvents of aqueous / organic mixtures. Examples of the pH of the liquid include pH 5.5-7.5, pH 6-7, and pH 6-6.5. The liquid may be stored at room temperature, refrigerated (e.g., 2-8°C), or frozen (e.g., -20°C or -80°C). When the composition of the present disclosure is solid, it can be prepared as a solid 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 solid, it can be dissolved and reconstituted with a suitable medium to prepare a liquid suitable for administration. Examples of suitable solvents for reconstituting the solid include water, saline, buffer solutions, phosphate-buffered saline, Ringer's (lactated or dextrose) solution, essential mineral medium, alcohol / water solution, dextrose solution, etc.

[0072] The composition of the present disclosure may further contain a pharmaceutically acceptable carrier, such as a suspending agent, solubilizing agent, stabilizer, isotonicity agent, preservative, anti-adsorption agent, surfactant, diluent, vehicle, pH adjuster, soothing agent, buffer, sulfur-containing reducing agent, antioxidant, etc. for administering the active ingredient, and these can be appropriately added within a range that does not impair the effects of the present disclosure.

[0073] The suspending agent is not particularly limited, and examples thereof include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, powdered tragacanth, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate, and the like.

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

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

[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 parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

[0078] The adsorption inhibitor 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, and polyethylene glycol.

[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, thiochitic acid, thiodiglycol, thioethanolamine, thioglycerol, thiosorbitol, thioglycolic acid and salts thereof, sodium thiosulfate, glutathione, and thioalkanoic acids having 1 to 7 carbon atoms.

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

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

[0082] In the composition of the present disclosure, the peptide can be modified in various ways in consideration of its tendency to be easily metabolized and excreted. Examples of such modifications include the addition of an alkyl chain, polyethylene glycol, or a sugar chain. Such modifications can increase the blood residence time of the composition of the present disclosure and reduce antigenicity.

[0083] The peptide of the present disclosure may be encapsulated in the composition of the present disclosure. The encapsulation can be achieved by using, for example, a biodegradable polymer compound such as polylactic acid glycol (PLGA), porous hydroxyapatite, liposomes, surface-modified liposomes, emulsions prepared with unsaturated fatty acids, nanoparticles, nanospheres, or the like as a sustained-release base.

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

[0085] The subject to which the composition of the present disclosure is administered is not particularly limited. When the composition of the present disclosure is used in vivo, the subject (subject to administration) can be, for example, the above-mentioned examples. When the composition of the present disclosure is used in vitro, the subject to administration can be, for example, cells, tissues, organs, etc., and examples of the cells include cells collected from a living body, cultured cells, etc., and examples of the tissue or organ include tissue (biological tissue) or organs collected from a living body, etc.

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

[0087] Examples of the central nervous system disease include mental disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, etc.), childhood mental disorders (attention deficit disorder, attention deficit / hyperactivity disorder, conduct disorder, autism, etc.), neurodegenerative disorders, neural stem cell disorders, neural precursor disorders, ischemic disorders, neurotraumatic disorders, emotional disorders, psychomotor disorders, sleep disorders (hypersomnia, circadian rhythm sleep disorders, insomnia, parasomnia, sleep deprivation, etc.), and mental disorders such as anxiety (acute stress disorder, generalized anxiety disorder, etc.). anxiety disorder, social anxiety disorder, panic disorder, post-traumatic stress disorder, agoraphobia, obsessive-compulsive disorder, etc.), factitious disorder (acute hallucinatory mania, etc.), impulse control disorder (compulsive gambling, intermittent explosive disorder, etc.), mood disorders (bipolar I disorder, bipolar II disorder, mania, mixed affective state, etc.), major depression, chronic depression, seasonal depression, psychotic depression, seasonal depression, cognitive disorders (amnesia, senile dementia, HIV-related dementia, Alzheimer's disease, Huntington's disease, dementia with Lewy bodies) , vascular dementia, drug-related dementia, tardive dyskinesia, myoclonic spasms, dystonia, delirium, Pick's disease, Creutzfeldt-Jakob disease, HIV disease, Gilles de la Tourette syndrome, epilepsy, muscle spasms, mild cognitive impairment, etc.), mental retardation (spasticity, Down syndrome, Fragile X syndrome, etc.); premenstrual syndrome (PMS), premenstrual dysphoric disorder (PDD), postpartum depression, neuronal injury disorders (eye injury, ocular retinopathy or macular degeneration, tinnitus, hearing impairment, cerebral edema) These include Parkinson's disease, Parkinson-like disorders, migraine, epilepsy, Alzheimer's disease, brain injury, stroke, cerebrovascular disease (cerebral arteriosclerosis, cerebral amyloid angiopathy, hereditary cerebral hemorrhage, cerebral hypoxia-ischemia, etc.), drug addiction (narcotic addiction, alcoholism, amphetamine addiction, cocaine addiction, nicotine addiction, drug withdrawal syndrome, etc.), eating disorders (anorexia, bulimia, binge eating disorder, pyophagia, obesity, compulsive eating disorder, pagophagia, etc.).

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

[0089] The composition of the present disclosure can be administered by, for example, intrathecal administration, intramuscular administration, subcutaneous administration, intravenous administration, or transdermal administration, but intramuscular or subcutaneous administration by injection or infusion is preferred because it can be administered safely and stably without depending on the skill of the administerer. Examples of the transdermal administration include iontophoresis.

[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 of the subject, i.e., an effective dose. The dosage can be appropriately determined depending on, for example, the age, weight, symptoms, etc. of the subject.

[0091] The composition of the present disclosure may be administered once or multiple times. The multiple times may be, for example, two, three, four, five, or more times. The number of administrations may be appropriately determined while confirming the effect on the subject. When administering multiple times, the administration interval may be appropriately determined while confirming the preventive effect on the subject, and may be, for example, once a day, once a week, once every two weeks, once a month, once every three months, or once every six months.

[0092] The composition of the present disclosure may prevent or alleviate at least one symptom caused by a central nervous system disease and / or brain metastatic cancer in a subject to which the composition is administered. Symptoms of central nervous system disease and / or brain metastatic cancer include headache, vomiting, visual impairment, impaired consciousness, seizures, paralysis, and speech disorders. The composition of the present disclosure may prevent or alleviate at least one symptom associated with central nervous system disease and / or brain metastatic cancer. The alleviation of the symptom may be evaluated subjectively or objectively, for example, by self-assessment by the subject; a physician's assessment; a quality of life (QOL) assessment; or an assessment of the delay in progression of symptoms of central nervous system disease and / or brain metastatic cancer, or the reduction in the severity of symptoms of central nervous system disease and / or brain metastatic cancer. The objective assessment may be an animal assessment or a human assessment.

[0093] The examination for brain metastatic cancer can be carried out using, for example, a computed tomography (CT) examination, a positron emission tomography (PET) examination, a magnetic resonance imaging (MRI) examination, or the like.

[0094] Examples of primary cancers of brain metastases include lung cancer, breast cancer, melanoma, renal cell carcinoma, kidney cancer, colon 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.

[0095] For the method of producing the composition of the present disclosure, see, for example, the method described later in Example 1. As an example, the composition of the present disclosure can be produced by mixing the drug, the peptide represented by formula (2), and the surfactant.

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

[0097] Before the mixing, the molecule containing an alkyl chain may be dissolved in DMSO, and after the dissolution, the peptide represented by formula (2) may be added to carry out the alkylation treatment of the peptide represented by 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 cognitive function of the present disclosure includes the composition of the present disclosure. According to the composition for use in improving cognitive function of the present disclosure, an effect of improving cognitive function can be obtained.

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

[0100] The composition for improving cognitive function of the present disclosure can improve cognitive function, for example, by being used on a subject. As a result, the composition for improving cognitive function of the present disclosure can achieve, for example, an effect of improving cognitive function. The use conditions (administration conditions) of the composition for improving cognitive function of the present disclosure can be referenced to the description of the use conditions of the composition of the present disclosure.

[0101] <Composition for use in inhibiting tumor growth in the brain> In another aspect, the present disclosure provides a composition capable of inhibiting tumor growth in the brain. The composition for use in inhibiting tumor growth in the brain of the present disclosure comprises the composition of the present disclosure. The composition for use in inhibiting tumor growth in the brain of the present disclosure can achieve an inhibitory effect on tumor growth in the brain.

[0102] The inhibition of tumor growth in the brain can be evaluated by measuring the size of the tumor, for example, by performing a CT scan, a PET scan, or an MRI scan.

[0103] The composition for use in suppressing brain tumor growth of the present disclosure can, for example, be used on a subject to suppress brain tumor growth. As a result, the composition for use in suppressing brain tumor growth of the present disclosure can, for example, achieve an inhibitory effect on brain tumor growth. The use conditions (administration conditions) of the composition for use in suppressing brain tumor growth of the present disclosure can be referenced to the description of the use conditions of the composition of the present disclosure.

[0104] <Use> In another aspect, the present disclosure relates to use of a composition of the present disclosure for use in a method for preventing and / or treating central nervous system diseases and / or brain metastatic cancer. The present disclosure also relates to use of a composition of the present disclosure for use in improving cognitive function and / or suppressing tumor growth in the brain. The use of the composition of the present disclosure can be referenced in the description of the composition of the present disclosure.

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

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

[0107] (1) Material Ac-c[Cys-Pro-Pro-Tyr-Leu-Pro-c(Lys-Tyr-Leu-Cys]-Asp)-Leu-Ile-NH ２ (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 synthesized by Scrum Co., Ltd. (Tokyo, Japan) according to the methods described in Patent Documents 1 and 2, respectively. 16:0 azidocaproyl PE (Cat No: 870126P-25mg) was purchased from Sigma-Aldrich, Cremophor EL (Cat No: 09727-14) from Nacalai Tesque, Inc., and ICG (Cat No: I0535) 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 dissolution, the solution was left to stand overnight at room temperature (approximately 25°C, the same applies below), and dipalmitoylated KS-487 was prepared by click reaction between the DBCO group and the azido group.

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

[0110] (3) Preparation of a composition containing ICG ICG was dissolved in DMSO to prepare composition A containing ICG but not containing KS-487 or Cremophor EL.

[0111] (4) Preparation of a composition containing ICG and Cremophor EL Composition B was prepared in the same manner as in Example 1(2) above, except that dipalmitoylated KS-487 was not added.

[0112] (5) Preparation of a composition containing ICG, dipalmitoylated KS-487, and Cremophor EL Composition C was prepared in the same manner as in Example 1(2) above, except that dipalmitoylated KS-487 was added in an amount 0.3 times the standard amount (1 time) of dipalmitoylated KS-487 in the composition of Example 1(2).

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

[0114] (6) Evaluation of Brain Delivery by Bioimaging The brain delivery of the compositions of the present disclosure was evaluated by bioimaging. Specifically, Compositions A to D prepared in Examples 1(2) to 1(5) were diluted 10-fold with PBS (final ICG concentration: 0.1 mg / ml). After dilution, 400 μl of each diluted composition was administered subcutaneously to BALB / cCrSlc mice (6 weeks old, n=3). Forty-eight hours after administration, the mice were perfused with PBS and their brains were harvested. Bioimaging was then performed using a VISQUE™ InVivo Smart-LF (VIEWWORKS). In the bioimaging, excitation wavelengths of 740-790 nm and fluorescence wavelengths of 810-860 nm were measured. Image analysis was performed using CleVue™ Software (VIEWWORKS). These results are shown in Figure 5.

[0115] Figure 5 shows bioimaging images and graphs demonstrating the brain penetration of Compositions A to D. Figure 5(A) shows, from left to right, a bright field, the front side of the brain observed under fluorescent light, the back side of the brain observed under fluorescent light, and a split section of the brain observed under fluorescent light. In Figure 5(B), the vertical axis represents fluorescence intensity, and the horizontal axis represents the type of composition. As shown in Figure 5, when Composition A consisting only of ICG was administered, almost no ICG-derived fluorescence was detected in the brain. When Composition B, which did not contain dipalmitoylated KS-487, was administered, slight ICG-derived fluorescence was detected in the brain. When Compositions C and D, which contained dipalmitoylated KS-487, ICG-derived fluorescence was detected in the brain in a concentration-dependent manner depending on the dipalmitoylated KS-487 added. These results demonstrate that compositions containing ICG, dipalmitoylated KS-487, and Cremophor EL are delivered to brain tissue when administered to peripheral tissues.

[0116] (7) Novel Object Recognition Test It has been reported that intranasal administration of the VIPR2 antagonist peptide KS-133 to mice significantly suppresses the phosphorylation of CREB, one of the downstream signals of VIPR2, in brain tissue (Reference 1). It has also been reported that subcutaneous administration of KS-133 to schizophrenia model mice during early postnatal development, when the blood-brain barrier is immature, suppresses cognitive decline (Reference 1). These findings suggest that KS-133 alters cognitive function when it reaches the brain tissue of schizophrenia model mice. Therefore, we investigated whether cognitive function would change when a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL was administered to schizophrenia model mice. Specifically, a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL (Composition E) was prepared. The preparation was carried out using the same method as in Example 1 (2), except that KS-133 was used instead of ICG. The schizophrenia model mice were produced using the method described in Japanese Patent Application No. 2020-059721 (International Publication No. 2021 / 200259). The VIPR2-selective agonist Ro25-1553 was subcutaneously administered once daily for 14 days to mice on day 1 of birth. After the subcutaneous administration, the mice (6 weeks old) were continued to be raised and grown. Composition E or saline was subcutaneously administered once daily for 14 days. For the subcutaneous administration, Composition E was diluted with saline to a concentration of 3 mg / kg of KS-133. 24 hours after the subcutaneous administration, object recognition training was performed. 24 hours after the subcutaneous administration, the mice were subjected to a novel object recognition test. The novel object recognition test was conducted during the light period (8:00-20:00) in accordance with Non-Patent Document 1. First, in a soundproof laboratory set at an illuminance of 30 lux, test mice were acclimatized in a test cage (30 cm x 30 cm x 35 cm) made of acrylic-modified polyvinyl chloride and lined only with sterilized wooden soft chips (Sankyo Labo Service Co., Ltd.) for 10 minutes per day for three consecutive days.On the fourth day of the test, two different objects (objects a and b were randomly selected from a golf ball, a Lego block, a plastic cylinder, and an electrical outlet) were placed 8 cm away from the wall, and the mice were allowed to freely explore for 10 minutes (training trial). 24 hours after the exploration, object b was replaced with a novel object c in the test cage, and the mice were allowed to freely explore for 5 minutes (test trial). The behavior of the mice in the training trial and test trial was videotaped, and the exploratory time for each of the two objects was measured. The percentage difference in the exploration time between object c and object a relative to the total exploration time in the test trial was calculated as a discrimination index. These results are shown in Figure 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] FIG. 6 is a graph showing the results of the test trials. In FIG. 6(A), the vertical axis represents exploratory time, and the horizontal axis represents the details of the administered drugs. In FIG. 6(B), the vertical axis represents discrimination index. As shown in FIG. 6(A), in the group administered with Composition E (n=16 / group), the exploratory time for the novel object was significantly longer than the exploratory time for the familiar object (p-value of Student's t-test: less than 0.05). On the other hand, in the control group administered with saline (n=16 / group), no significant difference in exploratory time was observed. Furthermore, as shown in FIG. 6(B), the discrimination index of the group administered with Composition E was significantly higher than that of the control group administered with saline (p-value of Student's t-test: less than 0.001). These results demonstrate that when a composition containing KS-133, dipalmitoylated KS-487, and Cremophor EL is administered to peripheral tissues, it is transported to brain tissues and improves cognitive function.

[0118] (8) Evaluation of the amount of KS-133 transferred to brain tissue by pharmacokinetic study. Composition E, which contains KS-133, dipalmitoylated KS-487, and Cremophor EL, was diluted with saline to prepare a drug solution with a KS-133 concentration of 2 mg / mL. After preparation, the drug solution was administered subcutaneously to male ICR mice at 10 mg / kg. Plasma, liver, cerebral cortex, and hypothalamus were collected 1, 3, 6, and 10 hours after administration, 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 study. As shown in Figure 7, the plasma KS-133 concentrations (nmol / ml) were 14.717, 22.465, 10.600, and 2.005 at 1, 3, 6, and 10 hours, respectively, or 19.112, 24.938, 13.369, and 1.008 at 1, 3, 6, and 10 hours, respectively. The peak plasma KS-133 concentration occurred 3 hours after administration. The hypothalamus KS-133 concentrations (nmol / g) were 0.074, 0.124, 0.027, and 0.015 at 1, 3, 6, and 10 hours, respectively, or 0.097, 0.137, 0.065, and 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 concentrations of KS-133 (nmol / g) in the cerebral cortex were 0.096, 0.121, 0.056, and 0.014 at 1, 3, 6, and 10 hours, respectively, or 0.105, 0.137, 0.068, and 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. The concentrations of KS-133 (nmol / g) in the liver were 3.642, 6.308, 3.796, and 0.941 at 1, 3, 6, and 10 hours, respectively, or 4.750, 8.292, 3.883, and 0.612 at 1, 3, 6, and 10 hours, respectively. The peak concentration of KS-133 in the liver occurred 3 hours after administration. The time course of KS-133 concentration in each tissue was well correlated. The results of this pharmacokinetic study demonstrated that administration of Composition E resulted in time-dependent transfer of KS-133 to brain tissues, such as the hypothalamus and cerebral cortex. These results strongly support the idea that the mechanism of efficacy exhibited 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 transferring from peripheral tissues to brain tissue and suppressing downstream signaling of VIPR2.

[0120] Although the present disclosure has been described above with reference to the embodiments and examples, the present disclosure is not limited to the above-described embodiments and examples. Various modifications that can be understood by a person 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 December 28, 2023, the disclosure of which is incorporated herein in its entirety by reference.

[0122] The patents, patent applications, and publications cited herein are incorporated by reference into this specification in their entirety as if the contents were specifically set forth herein.

[0123] <Supplementary Notes> Some or all of the above embodiments and examples can be described as in the following supplementary notes, but are not limited to the following: <Composition> (Supplementary Note 1) A composition comprising 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 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 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-diaminobutanoic 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 ２７represents 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 either absent or proline; X ３４ represents serine, threonine, cysteine, D-cysteine, or proline, the peptide of formula (2) has an alkyl chain at the N-terminus, C-terminus, or side chain of an amino acid directly or via a linker, and X ２３ or X ２４ and X ３４ is cysteine ​​or D-cysteine ​​when involved in cyclization, and forms a disulfide bond or a covalent bond between the respective -SH groups in the side chains via a linker such as a methylene group, an acetylmethylene group, an ethylene group, or a propylene group, and the peptide of formula (2) may have one cyclic structure in the molecule by the formation of a disulfide bond or a covalent bond between the respective -SH groups in the side chains. (Appendix 2) In 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-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline; X ３３ The composition according to claim 1, wherein X is not present. ２３ represents serine, threonine, cysteine, D-cysteine, or proline; X２４ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline; X ３３ The composition according to claim 1, wherein X represents proline. ２３ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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 (Appendix 5) The composition according to any one of Appendices 1 to 4, wherein the drug is a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), a derivative or modification thereof, or a pharmacologically 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 In the 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 １１represents 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 forms a disulfide bond between each side chain, and X ７ and X １１ form an amide bond between the respective side chains, and as a result of this formation, the peptide of formula (1) has two cyclic structures in the molecule, and the N-terminal amino group and the C-terminal carboxy group of the peptide of formula (1) may be modified or deleted. (Appendix 6) The composition according to any one of Appendices 1 to 5, wherein in formula (2), the number of carbon atoms in the alkyl chain is C10 or more. (Appendix 7) In 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 (Appendix 8) The composition according to any one of Appendices 1 to 7, wherein the peptide of (2) has an alkyl chain at the N-terminus via a linker. (Appendix 9) The composition according to any one of Appendices 1 to 8, wherein in formula (2), the linker contains PEG, and the average molecular weight of the PEG is 2000 or less. (Appendix 10) The linker is X Ｎ It is expressed as X Ｎ The composition according to any one of claims 1 to 9, wherein X is any 1 to 22 amino acid residues. 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. (Appendix 12) The composition according to any one of Appendices 1 to 11, wherein the content of the surfactant is 10% by mass or more, based on the total mass of the composition. (Appendix 13) The composition according to any one of Appendices 1 to 12, wherein the surfactant is selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid ester. (Appendix 14) The composition according to Appendices 13, wherein the surfactant is polyoxyethylene-35-ricinoleate or polysorbate 80. (Appendix 15) The composition according to any one of Appendices 1 to 14, further comprising dimethyl sulfoxide. (Appendix 16) The composition according to any one of Appendices 1 to 15, comprising a micelle, wherein the micelle is composed of 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 the surfactant, and wherein the micelle contains the drug. (Appendix 17) The composition according to any one of Appendices 1 to 16, for use in a method for preventing and / or treating a central nervous system disease and / or brain metastatic cancer. (Appendix 18) The composition according to any one of Appendices 1 to 17, which has brain-transporting properties. (Appendix 19) The composition according to any one of Appendices 1 to 18, for use in improving cognitive function.

[0124] As described above, the present disclosure can provide a composition and the like that is brain-localizable. Therefore, the present disclosure can be said to be extremely useful, for example, in the field of pharmaceuticals.

Claims

1. A composition comprising a drug, a linear peptide and / or cyclic peptide consisting of an amino acid sequence represented by the following formula (2), a derivative or modification 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 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-diaminobutanoic 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 represents either absent or proline; X ３４ represents serine, threonine, cysteine, D-cysteine, or proline, the peptide of formula (2) has an alkyl chain at the N-terminus, C-terminus, or side chain of an amino acid directly or via a linker, and X ２３ or X ２４ and X ３４ is cysteine ​​or D-cysteine ​​when involved in cyclization, and forms a covalent bond between the respective -SH groups in the side chains via a disulfide bond or a linker such as a methylene group, an acetylmethylene group, an ethylene group, or a propylene group, and the peptide of formula (2) may have one cyclic structure in the molecule by the formation of a disulfide bond or a covalent bond between the respective -SH groups in the side chains.

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-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline; X ３３ The composition of claim 1 , wherein is absent.

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-diaminobutanoic acid, ornithine, lysine, arginine, proline, cis-4-hydroxy-proline, or trans-4-hydroxy-proline; X ３３ The composition of claim 1 , wherein represents proline.

4. In the formula (2), X ２３ represents serine, homoserine, threonine, allothreonine, 2,3-diaminopropionic acid, 2,4-diaminobutanoic 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 The composition of claim 1 , wherein represents proline.

5. The composition according to any one of claims 1 to 4, wherein the drug is a cyclic peptide consisting of an amino acid sequence represented by the following formula (1), a derivative or modification thereof, or a pharmacologically 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 In the 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 represents 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 forms a disulfide bond between each side chain, and X ７ and X １１ form an amide bond between the respective side chains, and as a result of this formation, the peptide of formula (1) has two cyclic structures in the molecule, and the N-terminal amino group and the C-terminal carboxy group of the peptide of formula (1) may be modified or deleted.

6. The composition according to any one of claims 1 to 5, wherein in the formula (2), the number of carbon atoms in the alkyl chain is C10 or more.

7. 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 7. The composition according to claim 1, wherein the total amount of the hydroxybenzoates is 100% or more.

8. A composition described in any one of claims 1 to 7, wherein the peptide (2) has an alkyl chain at the N-terminus via a linker.

9. The composition according to any one of claims 1 to 8, wherein in formula (2), the linker comprises PEG, and the average molecular weight of the PEG is 2000 or less.

10. The linker is X Ｎ It is expressed as X Ｎ The composition of any one of claims 1 to 9, wherein is any 1 to 22 amino acid residues.

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 The composition according to claim 10, wherein the compound is represented by -Pro.

12. A composition according to any one of claims 1 to 11, wherein the content of the surfactant is 10% by mass or more, based on the total mass of the composition.

13. A composition according to any one of claims 1 to 12, wherein the surfactant is selected from the group consisting of polyoxyethylene castor oil and polyoxyethylene sorbitan fatty acid esters.

14. The composition of claim 13, wherein the surfactant is polyoxyethylene-35-ricinoleate or polysorbate 80.

15. The composition of any one of claims 1 to 14, further comprising dimethyl sulfoxide.

16. A composition according to any one of claims 1 to 15, comprising a micelle, the micelle being composed of a linear peptide and / or a cyclic peptide consisting of an amino acid sequence represented by formula (2), a derivative or modification thereof, or a pharmacologically acceptable salt thereof, and the surfactant, and the micelle containing the drug.

17. A composition according to any one of claims 1 to 16 for use in a method for the prevention and / or treatment of central nervous system diseases and / or brain metastatic cancer.

18. A composition described in any one of claims 1 to 17, which has brain-transmitting properties.

19. A composition according to any one of claims 1 to 18 for use in improving cognitive function.

Images