JP2016108323A - Novel functional peptide - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a peptide having high binding affinity to glucosaminoglycan which promotes adhesion between biological tissue promote or adhesion between administered glucosaminoglycan and biological tissue, and a medical drug and cosmetic containing the peptide.SOLUTION: There are provided a functional peptide that promotes adhesion between glucosaminoglycan expressed by specific amino acid sequence and biological tissue or a derivative peptide thereof, and a medical drug and cosmetic which contain pharmaceutically acceptable salt or a solvate thereof, the peptide or the like.SELECTED DRAWING: None

Description

  The present invention relates to a novel functional peptide or a derivative thereof. Moreover, this invention relates to the pharmaceutical or cosmetics containing the said functional peptide.

  Glucosaminoglycan is a polysaccharide having an amino sugar in the molecule, and has a basic structure of a disaccharide repeating structure composed of uronic acid and glucosamine or galactosamine. Glucosaminoglycans can be divided into hyaluronic acid, chondroitin sulfate, deltaman sulfate, heparan sulfate, etc., for example, hyaluronic acid is widely present in the extracellular matrix in vivo such as joints, vitreous, skin, brain, Chondroitin sulfate is known to exist in all tissues including the extracellular matrix of cartilage and connective tissues such as skin.

  These glucosaminoglycans interact with various cell growth factors and extracellular matrix components to control cell activities such as cell adhesion, migration, proliferation, differentiation, and morphogenesis, as well as diseases such as inflammation and cancer cell metastasis. Since it is known that it is also related to a general phenomenon, various studies have been conducted on the influence and mechanism of glucosaminoglycan on living bodies. In addition, glucosaminoglycan is known to exhibit extremely high water retention ability and viscoelasticity, and this property is used to treat various diseases in various fields including ophthalmology and dermatology. It is applied clinically as a medicine and a preventive drug.

  For example, in the field of ophthalmology, with the recent increase in the use of contact lenses and the chance to see monitors such as personal computers and games, the secretion of tears has decreased and the composition of tears has changed even if the amount is sufficient. By doing so, an increasing number of people have symptoms of dry eyes that are in a state where the power to moisturize the eyes is reduced (Non-Patent Document 1). As a drug for relieving such dryness of the eyes, an eye drop containing sodium hyaluronate, which is a kind of glucosaminoglycan, as an active ingredient is known. Sodium hyaluronate preparations as ethical drugs are intrinsic diseases such as Sjogren's syndrome, Stevens-Johnson syndrome, dry eye syndrome (dry eye), and exogenous diseases due to postoperative, drug, trauma, wearing contact lenses, etc. Efficacy and effects are keratoconjunctival epithelial disorder associated with any of these diseases. Thus, the sodium hyaluronate preparation has a wide range of applications and is a useful medicine, but the problem that the instilled medicine flows down from the cornea by tears requires 5 to 6 eye drops per day. Is left.

  In the dermatological field, for example, an external preparation containing a heparin-like substance that is a kind of glucosaminoglycan as an active ingredient is known, such as sebum deficiency, progressive palmokeratoderma or atopic dermatitis, etc. Has been used to treat. In the cosmetic field, lotions containing hyaluronic acid, a kind of glucosaminoglycan, are commercially available. Also in these external preparations and cosmetics, if the active ingredient stays in the skin for a long period of time, the effect will be sustained as much, so that those having such properties are desirable.

In addition, as described above, glucosaminoglycans are widely present in the extracellular matrix in the living body and connective tissues such as the skin. Therefore, the glucosaminoglycan is not only present as a therapeutic agent but also already present in the living body. Application to treatment of diseases using glycans is also expected. One such disease is, for example, retinal detachment. Retinal detachment refers to a state in which the neural retina has been detached from the retinal pigment epithelium. First of all, there is a laser photocoagulation method. If a retinal tear has only occurred, laser irradiation from the pupil to the periphery of the retinal tear can be prevented, and retinal detachment that may occur in the future can be prevented by strengthening retinal adhesion around the tear hole. If retinal detachment has already occurred, a vitrectomy is performed in which a surgical instrument is inserted into the vitreous and the retina is restored from within the eye. However, in intractable cases, the retina detaches even after vitrectomy. In this case, prevention of redetachment can be expected by improving the adhesion between the retina and the retinal pigment epithelium. The extracellular matrix present in the gap between the neural retina and the retinal pigment epithelium, especially hyaluronic acid, which is a glucosaminoglycan, is abundant. If there is an action that promotes adhesion of the retina using this extracellular matrix, it is considered that it contributes to an increase in the success rate of vitrectomy.

On the other hand, hyaluronic acid (HA) is a simple structure composed of repeating N-acetylglucosamine and glucuronic acid disaccharides. Many types of proteins that bind to hyaluronic acid in vivo (HABP: hyaluronic acid binding protein) have been reported, but the mode of binding to hyaluronic acid can be roughly divided into two. That is, among HABPs, HABPs such as aggrecan, versican (also referred to as versican, PG-M), neurocan (neurocan), blebican (also referred to as brevican, BEHAB), and the like, have about 100 amino acids in the N-terminal region. The spherical three-dimensional structure (G1 domain) as shown shows hyaluronic acid binding activity. On the other hand, HABP such as SPACR (Sialoprotein Associated Cones and Rods) and SPARCCAN (Sialoproteolyc Associated with Cones and Rods) and the like is composed of nine amino acids composed of nine amino acids called B (X ₇ ) B. (Non-Patent Document 2). In recent years, it has been reported that a peptide created based on the G1 domain of versican assists the binding between hyaluronic acid and cornea and can be a novel medical material (Patent Document 1), B (X ₇ ) B There is no such report on peptides created based on this.

JP 2004-154038 A

Ministry of Health, Labor and Welfare, “Study Report on Candidate Ingredients Possible to Use as OTC Drugs among Active Ingredients in OTC Drugs”, 2011, pp87-95 Masahiko Yoneda et al., Cell Engineering, 2001, 20th, 8th, pp1114-1121

  An object of the present invention is to provide a functional peptide or a derivative thereof that promotes adhesion between living tissues or promotes adhesion between glucosaminoglycan administered as an active ingredient and living tissues.

As a result of intensive studies to solve such a problem, the present inventors have found that a peptide consisting of the following amino acids far exceeds a peptide derived from a living body and has a glucosaminoglycan binding ability, particularly hyaluronic acid binding ability, hyaluronic acid -It has been found that it exhibits a binding assisting action between the cornea and between the retina and the retinal epithelium, and the present invention has been completed.
That is, the present invention relates to the following inventions.

[1] Peptides represented by the following general formula (1) or general formula (2), derivatives thereof, pharmaceutically acceptable salts or solvates thereof (however, represented by SEQ ID NOs: 3 to 6) Excluding peptides consisting of amino acid sequences).
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[2] The peptide represented by the general formula (1) or the general formula (2) according to the above [1], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is basic The amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, the branched amino acid is Leu, Ile or Val, the amide-containing amino acid is Asn or Gln, and the hydroxy-containing amino acid is Ser. Or the peptide, its derivatives, their pharmaceuticals, wherein Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid is Cys or Met. Top acceptable salts or solvates thereof.
[3] A peptide represented by the general formula (1) described in [1] or [2] above, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The peptide, derivative thereof, pharmaceutically acceptable salt or solvate thereof.

[4] A peptide represented by the general formula (2) described in [1] or [2] above, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The peptide, derivative thereof, pharmaceutically acceptable salt or solvate thereof.
[5] The peptide, derivative thereof, pharmaceutically acceptable salt or solvate thereof according to the above [1] or [2], wherein the amino acid sequence is represented by SEQ ID NOs: 7 to 38.
[6] The above [1] or [2], wherein the amino acid sequence is represented by SEQ ID NO: 15, 27, or 28
Or a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[7] A medicament comprising, as an active ingredient, a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[8] The pharmaceutical according to [7] above, wherein the basic amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, and the branched amino acid is Leu, Ile or Val, The amide-containing amino acid is Asn or Gln, the hydroxy-containing amino acid is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid Wherein said pharmaceutical is Cys or Met.
[9] A medicament containing, as an active ingredient, the peptide represented by the general formula (1) according to the above [7] or [8], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. There,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to [7] or [8] above.
[10] A medicament containing, as an active ingredient, the peptide represented by the general formula (2) described in [7] or [8], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. There,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to [7] or [8] above.

[11] The above [7] or [8], comprising as an active ingredient a peptide consisting of the amino acid sequence represented by SEQ ID NOs: 3 to 38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. The medicament according to 1.
[12] The above [7] or [7] containing a peptide consisting of the amino acid sequence represented by SEQ ID NO: 15, 27 or 28, a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient 8] The medicine according to [8].
[13] The medicament according to any one of [7] to [12], which is used for prevention and / or treatment of eye diseases.
[14] The medicament according to [13] above, wherein the eye disease is retinal detachment.
[15] The medicament according to [14] above, wherein the retinal disease is retinal detachment, diabetic retinopathy or macular degeneration.

[16] Administration to a patient in need of a therapeutically effective amount of a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof A method for preventing and / or treating an eye disease, comprising the step of:
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[17] Peptides represented by the following general formula (1) or general formula (2), their derivatives, and their pharmaceutically acceptables for the manufacture of a medicament for the prevention and / or treatment of eye diseases Use of salts or solvates thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[18] (A) a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) A medicine containing glucosaminoglycan or a salt thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[19] The pharmaceutical according to [18] above, wherein the basic amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, and the branched amino acid is Leu, Ile or Val, The amide-containing amino acid is Asn or Gln, the hydroxy-containing amino acid is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid Wherein said pharmaceutical is Cys or Met.

[20] The component (A) is a peptide represented by the general formula (1) described in [18] or [19], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. And
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicament according to [18] or [19] above.

[21] The component (A) is a peptide represented by the general formula (2) described in [18] or [19], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. ,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicament according to [18] or [19] above.

[22] The above [18] or [19], wherein the component (A) is a peptide comprising the amino acid sequence represented by SEQ ID NO: 3-38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. ] The medicine as described in].
[23] The above [18], wherein the component (A) is a peptide comprising the amino acid sequence represented by SEQ ID NO: 15, 27, or 28, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [19] The medicament according to [19].
[24] The medicament according to any of [18] to [23] above, wherein component (B) is hyaluronic acid or a salt thereof.
[25] The medicament according to any one of [18] to [24] above, which is used for prevention and / or treatment of an eye disease or skin disease.

[26] The medicament according to [25] above, wherein the eye disease is keratoconjunctival epithelial disorder.
[27] The medicament according to [26] above, wherein the keratoconjunctival epithelial disorder is dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion or corneal ulcer.
[28] The medicament according to [25] above, wherein the skin disease is sebum deficiency, progressive palmar keratoderma, or atopic dermatitis.
[29] The medicament according to any one of [18] to [28], which is in the form of a pharmaceutical composition comprising the component (A) and the component (B) in the same preparation.
[30] The medicament according to any one of [18] to [28] above, which is in the form of a kit preparation comprising component (A) and component (B) in separate preparations.

[31] (A) a therapeutically effective amount of a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) A method for preventing and / or treating an eye disease or skin disease, comprising a step of separately administering to a patient in need of a therapeutically effective amount of glucosaminoglycan or a salt thereof simultaneously or at different times.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[32] (A) A peptide represented by the following general formula (1) or general formula (2), a derivative thereof, or the like for the manufacture of a medicament for the prevention and / or treatment of eye diseases or skin diseases Of (B) glucosaminoglycan or a salt thereof, and a pharmaceutically acceptable salt thereof or a solvate thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.

[33] (A) a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) Cosmetics containing glucosaminoglycan or a salt thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.
[34] The cosmetic according to [33], wherein the basic amino acid is Arg, His, or Lys, the acidic amino acid is Asp or Glu, and the branched amino acid is Leu, Ile, or Val. The amide-containing amino acid is Asn or Gln, the hydroxy-containing amino acid is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid Wherein said cosmetic is Cys or Met.

[35] The component (A) is a peptide represented by the general formula (1) described in [33] or [34], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. And
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
Cosmetics according to the above [33] or [34].

[36] The component (A) is a peptide represented by the general formula (2) described in [33] or [34], a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. ,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
Cosmetics according to the above [33] or [34].

[37] The above [33] or [34, wherein the component (A) is a peptide consisting of the amino acid sequence represented by SEQ ID NOs: 3 to 38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. ] Cosmetics.
[38] The above [33] to [33], wherein the component (A) is a peptide comprising the amino acid sequence represented by SEQ ID NO: 15, 27 or 28, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. [37] The cosmetic according to any one of [37].
[39] The cosmetic according to [33] or [34] above, wherein the component (B) is hyaluronic acid or a salt thereof.
[40] The cosmetic according to any one of [33] to [39], which is in the form of a composition comprising the component (A) and the component (B) in the same preparation.
[41] The cosmetic according to any one of [33] to [39], which is in the form of a kit containing the component (A) and the component (B) in separate preparations.

  The peptides of the present invention, their derivatives, their pharmaceutically acceptable salts, or their solvates have a binding ability for glucosaminoglycans far exceeding that of peptides derived from living organisms. And since glucosaminoglycan exists in every connective tissue of the living body, the peptide of the present invention can be used for the treatment and prevention of diseases that can be treated by improving the connectivity between living tissues, such as retinal detachment. Can be used.

  In addition, when the peptide of the present invention and glucosaminoglycan are administered in combination, the active ingredient glucosaminoglycan is stronger than the glucosaminoglycan present in the living tissue via the peptide of the present invention at the administration site. Join. Therefore, the glucosaminoglycan administered as an active ingredient stays at the application site for a long period of time, and as a result, the pharmacological effect of the glucosaminoglycan is significantly sustained as compared with the conventional one. In particular, the peptides of the present invention, their derivatives, their pharmaceutically acceptable salts, or their solvates can suppress hyaluronic acid efflux from the cornea and further assist the binding between hyaluronic acid and cornea. And can provide a highly durable drug.

The peptide of the present invention is a glucosaminoglycan other than hyaluronic acid, such as chondroitin (chn), chondroitin sulfate A (CSA), chondroitin sulfate C (CSC), dermatan sulfate (DS), heparan sulfate (HS), Since heparin (hep) and the like have a much higher binding ability than a peptide derived from a living body, the peptide of the present invention is not limited to one containing hyaluronic acid as an active ingredient. It can also be applied to drugs containing noglycan as an active ingredient.

  Furthermore, since the peptide of the present invention binds via glucosaminoglycan present in living tissue, the application of the peptide of the present invention is not limited to the retina and cornea. It can be applied to any living tissue that exists.

FIG. 1 is a graph showing the results of Test 1 (comparison test of binding activity between biotinylated hyaluronic acid and each peptide). FIG. 2 is a graph showing the results of Test 2 (comparison test of binding activity between biotinylated heparan sulfate and each peptide). FIG. 3 is a graph showing the results of Test 3 (combined activity comparison test between biotinylated chondroitin sulfate A and each peptide). FIG. 4 is a graph showing the results of Test 4 (combined activity comparison test between biotinylated chondroitin sulfate C and each peptide). FIG. 5 is a photograph showing the appearance of the porcine cornea surface after Test 5 (application of peptide + hyaluronic acid to the cornea). FIG. 6 is a photograph showing the appearance of the porcine cornea surface after Test 6 (application of peptide + chondroitin sulfate to the cornea). FIG. 7 is a graph showing the results of Test 7 (peeling retinal adhesion ability of the peptide of the present invention).

The terms used in this specification are used in the meaning normally used in the art unless otherwise specified. The present invention is described in further detail below.
“Basic amino acid” means an amino acid having a basic side chain, and includes arginine (Arg), histidine (His), lysine (Lys), and the like.
“Acid amino acid” means an amino acid having an acidic side chain, and examples thereof include aspartic acid (Asp) and glutamic acid (Glu).
“Branched amino acid” means an amino acid having a branched alkyl side chain, and includes leucine (Leu), isoleucine (Ile), valine (Val) and the like.
“Amido-containing amino acid” means an amino acid having an amide or carbamoyl group in the side chain, and includes asparagine (Asn), glutamine (Gln) and the like.
“Hydroxy-containing amino acid” means an amino acid having a hydroxyl group in the side chain, and examples thereof include serine (Ser) and threonine (Thr).
Examples of “aliphatic amino acids” include alanine (Ala) and glycine (Gly).
Examples of the “aromatic amino acid” include phenylalanine (Phe), tryptophan (Trp), tyrosine (Tyr) and the like.
“Sulfur-containing amino acid” means an amino acid having a sulfur atom in the side chain, and includes cysteine (Cys), methionine (Met) and the like.
As “glucosaminoglycan”, hyaluronic acid (HA), chondroitin (chn), chondroitin sulfate A (CSA), chondroitin sulfate C (CSC), dermatan sulfate (DS), heparan sulfate (HS), heparin (hep) And heparin-like substances.

“Derivative of peptide” means a polypeptide having substantially the same biological function or activity as the polypeptide of the present invention. A modified polypeptide in which the N-terminus of the polypeptide derivative is modified with an acyl group such as an acetyl group or other modifying group, and the carboxyalkyl group at the C-terminus of the polypeptide derivative is converted to a carboxylate, amide, ester, or the like. Polypeptides are also encompassed by the invention. Furthermore, polypeptides that have been PEGylated for the purpose of extending the blood half-life and polypeptides to which sugar chains have been added are also encompassed by the present invention.

  “Pharmaceutically acceptable salts” include physiologically acceptable salts with acids or bases, and acid addition salts are particularly preferred as pharmaceutically acceptable salts of peptides. Examples of such salts include salts with inorganic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid, or acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, Salts with organic acids such as malic acid, succinic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid are used. Examples of glucosaminoglycan salts include sodium salts and calcium salts.

As a “solvate”, any number of solvates may be coordinated with the peptide of the present invention. Preferably a hydrate is mentioned.
The “pharmaceutical composition” only needs to contain at least the peptide of the present invention, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Examples of “eye diseases” include, but are not limited to, retinal diseases and keratoconjunctival epithelial disorders. Examples of retinal diseases include retinal detachment, diabetic retinopathy, macular degeneration, and the like. Examples of the keratoconjunctival epithelial disorder include dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion, and corneal ulcer.
Examples of “skin diseases” include sebum deficiency, progressive palmar keratoderma, or atopic dermatitis.

Arginine (Arg) and lysine (Lys) are preferable as the basic amino acids in X ¹ , X ² and X ⁹ of the peptide of the present invention.
The acidic amino acid in X ¹ and X ⁴ of the peptide of the present invention is preferably glutamic acid (Glu).
As branched amino acids in X ¹ , X ³ , X ⁴ and X ⁵ of the peptide of the present invention, leucine (Leu), isoleucine (Ile) and valine (Val) are preferable.
As the amide-containing amino acid in X ² , X ⁴ and X ⁷ of the peptide of the present invention, asparagine (Asn) and glutamine (Gln) are preferable.
As the hydroxy-containing amino acid in X ³ and X ⁶ of the peptide of the present invention, serine (Ser) and threonine (Thr) are preferable.
As the aliphatic amino acid in X ⁴ and X ⁷ of the peptide of the present invention, alanine (Ala) and glycine (Gly) are preferable.

The aromatic amino acid at X ⁸ of the peptide of the present invention is preferably phenylalanine (Phe).
As the sulfur-containing amino acid in Y ¹ and Y ² of the peptide of the present invention, cysteine (Cys) is preferable.
Examples of intramolecular bonds at Y ¹ and Y ² of the peptide of the present invention include peptide bonds and disulfide bonds, and disulfide bonds are preferred.
As X ¹ of the peptide of the present invention, arginine (Arg), lysine (Lys), glutamic acid (Glu), and leucine (Leu) are preferable, and arginine (Arg) and lysine (Lys) are particularly desirable.
X ² of the peptide of the present invention is preferably arginine (Arg), asparagine (Asn), or glutamine (Gln), and particularly preferably arginine (Arg) or glutamine (Gln).

X ³ of the peptide of the present invention is preferably leucine (Leu), isoleucine (Ile), valine (Val), or serine (Ser), and particularly preferably leucine (Leu) or serine (Ser).
X ⁴ of the peptide of the present invention is preferably glutamic acid (Glu), leucine (Leu), isoleucine (Ile), valine (Val), asparagine (Asn), or alanine (Ala), particularly glutamic acid (Glu), valine. (Val), asparagine (Asn), and alanine (Ala) are desirable.
X ⁵ of the peptide of the present invention is preferably leucine (Leu), isoleucine (Ile) or valine (Val), and particularly preferably leucine (Leu) or isoleucine (Ile).
X ⁶ of the peptide of the present invention is preferably leucine (Leu), isoleucine (Ile), valine (Val), or threonine (Thr), and particularly preferably leucine (Leu) or threonine (Thr).
As X ⁷ of the peptide of the present invention, asparagine (Asn), glutamine (Gln), and glycine (Gly) are preferable, and asparagine (Asn) and glycine (Gly) are particularly desirable.
X ⁸ of the peptide of the present invention is preferably phenylalanine (Phe), tryptophan (Trp), or tyrosine (Tyr), and particularly preferably phenylalanine (Phe).
X ⁹ of the peptide of the present invention is preferably arginine (Arg) or lysine (Lys).

  Peptides preferably used in the present invention are peptides consisting of the amino acid sequences represented by SEQ ID NOs: 3-38, derivatives thereof, pharmaceutically acceptable salts thereof, or solvates thereof. It has the structure shown in Table 1.

  The method for producing the peptide of the present invention is not particularly limited, and can be produced according to a known peptide synthesis method based on the amino acid sequence. The peptide synthesis method may be, for example, either a solid phase synthesis method or a liquid phase synthesis method. For example, in the solid-phase synthesis method, a peptide or amino acid that can constitute a peptide compound such as Fmoc method (fluorenylmethyloxycarbonyl method) and tBoc method (t-butyloxycarbonyl method) is condensed with the remaining part to produce a product. When has a protecting group, the desired peptide compound can be produced by removing the protecting group. For solid phase synthesis, APEX396 (manufactured by Advanced Chemtech), 433A (manufactured by Applied Biosystems), PS3 (manufactured by Protein Technologies), 9050 (manufactured by Perceptive), PSSM-8 (manufactured by Shimadzu Corporation), etc. The peptide synthesizer is commercially available. The resin used in the solid phase synthesis method is not particularly limited, and for example, Rink amide AM Resin, Fmoc-AA-Wang Resin, and AA-2-Cl-Trt Resin can be used. In the case of the liquid phase synthesis method, the peptide compound can be produced by a method in which N-protected amino acid derivatives are condensed step by step step by step. Depending on the presence or absence of a protecting group, a dicyclohexylcarbodiimide (DCC) method, an active ester method, a mixed acid anhydride method, or the like can be used. Also, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC · HCl), (1H-benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP) reagent, diisopropyl The target peptide compound can also be produced by a method using a condensing agent such as carbodiimide (DIPCDI).

  The method for producing the derivative of the peptide of the present invention is not particularly limited, and can be produced by a method usually used in the art. For example, the derivative can be produced by an acylation reaction with acetic anhydride or acetyl chloride for the amino group of the peptide or an amidation reaction with ammonia for the carboxyl group of the peptide. Moreover, after removing the protecting group of cysteine which is a constituent amino acid of the polypeptide, a cyclized peptide having a disulfide bond can be produced by using a method such as air oxidation or iodine oxidation. Moreover, when the protecting group of the thiol group contained in cysteine is an acetamidomethyl group, deprotection and disulfide bond generation can be simultaneously performed by using iodine.

  Moreover, a polynucleotide (DNA or RNA) corresponding to the amino acid sequence of the peptide of the present invention can be produced, and the peptide of the present invention can be produced by a genetic engineering technique using the polynucleotide.

The produced peptide of the present invention can be purified by protein isolation and purification methods generally known in the field of protein chemistry. Specifically, for example, extraction, recrystallization, salting out with ammonium sulfate or sodium sulfate, centrifugation, dialysis, ultrafiltration, adsorption chromatography, ion exchange chromatography, hydrophobic chromatography, normal phase chromatography, reverse Examples include phase chromatography, gel filtration, gel permeation chromatography, affinity chromatography, electrophoresis, countercurrent distribution, and combinations thereof.

  The peptide of the present invention has a strong binding ability to glucosaminoglycans such as hyaluronic acid, heparan sulfate, and chondroitin sulfate as confirmed in the experimental examples described later. Therefore, the peptide of the present invention can be used as an active ingredient in the prevention or treatment of diseases that can be treated by improving the connectivity between living tissues, for example, retinal detachment. Moreover, the peptide of this invention can be used as an adjuvant which improves the sustainability of glucosaminoglycan in the prevention or treatment of the disease conventionally treated with glucosaminoglycan. Examples of such diseases include keratoconjunctival epithelial disorders such as dry eye, dry keratoconjunctivitis, punctate superficial keratosis, corneal erosions, corneal ulcers, and other skin diseases such as sebum deficiency, progressive as described above. Examples include palmar keratoderma or atopic dermatitis.

  When the peptide of the present invention is used as an active ingredient, the medicament used for the prevention or treatment of various diseases includes the peptide of the present invention, its derivatives, their pharmaceutically acceptable salts, or their solvates. It only has to be. For example, the above-mentioned medicament may be composed only of the polypeptide of the present invention, or a composition comprising the peptide of the present invention, a derivative thereof, a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical carrier. It may be in the form of a thing.

  In addition, when the peptide of the present invention is used as an auxiliary agent, (A) the peptide of the present invention, a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof and (B) gluco What is necessary is just to contain saminoglycan or its salt. For example, the above-mentioned medicament may be composed only of the polypeptide of the present invention and glucosaminoglycan, and the peptide of the present invention, its derivative, their pharmaceutically acceptable salt or their solvate, It may be in the form of a composition comprising saminoglycan or a salt thereof and a pharmaceutical carrier. In addition, the above medicament may be in the form of a kit preparation comprising the peptide of the present invention and glucosaminoglycan in separate preparations.

  The pharmaceutical carrier that can be used for the above-mentioned medicament of the present invention is not particularly limited, and is pharmaceutically acceptable excipient, binder, lubricant, colorant, disintegrant, buffer, isotonic agent, dissolution agent. Adjuvants, chelating agents, stabilizers, preservatives, antioxidants, bases, emulsifiers and the like can be used.

Preferable examples of the excipient include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, soft Examples thereof include anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate, xylitol, sorbitol, and erythritol.
Preferable examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, polyethylene glycol 6000, and the like.
Preferable examples of the colorant include water-soluble colored tar dyes such as edible dyes such as edible red Nos. 2 and 3, edible yellows 4 and 5, edible blue Nos. 1 and 2, and aluminum salts thereof. Examples include insoluble lake pigments, natural pigments such as β-carotene, chlorophyll, bengara, and the like.

Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, soft anhydrous silicic acid, calcium carbonate and the like. .
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate and citrate.
Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, xylitol, fructose and the like.
Preferable examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.

Preferable examples of the chelating agent include edetates such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or salts thereof , Sodium hexametaphosphate, citric acid and the like.
Preferable examples of the stabilizer include sodium bisulfite.
Suitable examples of preservatives include sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoate such as butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride Quaternary ammonium salts such as benzethonium chloride and cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine and the like.

Preferable examples of the antioxidant include sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol and the like.
Preferable examples of the solubilizer include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, D-mannitol and the like.
Preferable examples of the base include hydrocarbons such as petrolatum, liquid paraffin, squalane, esters such as beeswax, jojoba oil, carnauba wax, triglycerides other than oleic acid triglycerides, fats and oils such as olive oil and beef tallow, Examples include higher alcohols such as cetanol, stearyl alcohol, and behenyl alcohol, higher fatty acids such as stearic acid, oleic acid, and behenic acid, lower alcohols such as ethanol and propanol, and water.
Suitable examples of emulsifiers include nonionic surfactants such as fatty acid monoglycerides, sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil, higher fatty acid salts, sodium lauryl sulfate, alkylsulfosuccinic acid esters, and the like. Examples include surfactants, cationic surfactants such as quaternary alkylamine salts, and amphoteric surfactants such as alkylbetaines.

It is desirable to use the most effective route for treatment, and oral administration, injection, transdermal formulation or eye drops can be used. preferable. The peptide of the present invention can also be directly applied to a living tissue to be treated. As such an embodiment, for example, it can be applied directly to the retina during vitreous surgery for retinal detachment. Examples of oral preparations include tablets (including sublingual tablets and orally disintegrating agents), capsules (including soft capsules and microcapsules), powders, granules, troches, syrups, emulsions, suspensions, and the like. . Examples of the injection include intradermal injection, subcutaneous injection, intravenous injection, intramuscular injection, intrathecal injection, epidural injection, local injection, and intraocular injection. Examples of transdermal preparations include patches, ointments, creams, lotions, and sprays. These preparations may be controlled-release preparations (including sustained-release microcapsules) such as immediate-release preparations or sustained-release preparations. The eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments, and the like. Moreover, as a formulation for applying directly to a biological tissue, the liquid agent etc. which have the composition similar to an aqueous eye drop are mentioned.

  In the case of producing an oral preparation, it is produced by, for example, adding an excipient, a disintegrant, a binder, or a lubricant to the peptide of the present invention and compressing it. Furthermore, for the purpose of taste masking, enteric dissolution or sustained release, the oral preparation may be coated by a method known per se. In the case of producing an injection, it is produced by dissolving, suspending or emulsifying the peptide of the present invention in an aqueous solvent or oily solvent together with a dispersing agent, a preservative, an isotonic agent and the like. At this time, additives such as a solubilizing agent, a suspending agent, a buffering agent, a stabilizer, a soothing agent and a preservative may be used as necessary. Furthermore, when manufacturing a transdermal formulation, it manufactures by making the peptide of this invention into a solid-state, semi-solid-state, or a liquid composition. For example, a solid composition is produced by powdering an active ingredient as it is, or by adding and mixing an excipient, a thickener and the like. The liquid composition is produced in almost the same manner as in the case of an injection. The semi-solid composition is produced, for example, by adding the peptide of the present invention to the above-mentioned base and mixing, and if necessary, the base is mixed with an emulsifier and the above-mentioned other components. Also good. In addition, any of these compositions may contain a pH adjuster, a preservative, and the like. Further, for example, the eye drop is prepared by dissolving or suspending the desired components in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil. The osmotic pressure can be adjusted to a sterilization treatment such as filtration sterilization. The preparation for direct application is prepared by, for example, dissolving or suspending the desired components in an aqueous solvent such as sterilized purified water or physiological saline, adjusting the osmotic pressure to a predetermined level, and performing sterilization such as filtration sterilization. Can be manufactured.

  The dose and frequency of administration of the medicament of the present invention vary depending on the administration form, patient age, body weight, nature or severity of the condition to be treated. For example, the peptide of the present invention is used directly as an active ingredient in living tissue. When applied, the peptide of the present invention is usually administered once to several times a day so that the amount of the peptide of the present invention is about 0.01 μg to 5 mg per adult, and more preferably about 0.0. Administer once or twice a day to give 1 μg to 3 mg. In particular, when applying directly to the retina during vitrectomy for retinal detachment, about 0.5 μg to 50 μg of the peptide of the present invention is applied to the retina.

In addition, when the peptide of the present invention is instilled as an adjuvant, it is usually once to several times a day so that the peptide of the present invention is about 0.01 μg to 1000 mg and the glucosaminoglycan is about 0.1 mg to 1000 mg per adult. More preferably, it is administered 1 to 4 times a day so that the peptide of the present invention is about 0.01 μg to 1000 mg and glucosaminoglycan is 0.1 mg to 30 mg per adult. Furthermore, when the peptide of the present invention is administered transdermally as an adjuvant, it is usually so that the amount of the peptide of the present invention is about 0.01 μg to 1000 mg and the amount of glucosaminoglycan is about 0.1 mg to 1000 mg per adult. It is administered once to several times a day, and more preferably, it is administered once or twice a day so that the amount of the peptide of the present invention is about 0.01 μg to 1000 mg and the amount of glucosaminoglycan is 1 mg to 300 mg per adult.

  Furthermore, as described above, glucosaminoglycan has an extremely high water retention ability, so when applied to the skin, it can moisturize the skin and improve or maintain the gloss and firmness of the skin. Therefore, the present invention also relates to a cosmetic containing (A) a peptide, a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof and (B) a glucosaminoglycan or a salt thereof. The cosmetic product of the present invention may be composed of, for example, the polypeptide of the present invention and glucosaminoglycan alone, as well as the above-mentioned pharmaceutical, and the peptide of the present invention, its derivatives, and their pharmaceutically acceptable products. It may be in the form of a composition comprising a salt or a solvate thereof, glucosaminoglycan or a salt thereof, and a carrier used in cosmetics. Further, the cosmetic of the present invention may be in the form of a kit comprising the peptide of the present invention and glucosaminoglycan in separate preparations. In the above, examples of the “carrier used in cosmetics” include the same pharmaceutical carriers as those used in the above-mentioned transdermal preparation, and the production method and application method thereof are the same as those of the above-mentioned transdermal preparation. is there.

  Hereinafter, the present invention will be described more specifically with reference to examples. These examples are provided for the purpose of illustration and are not intended to limit the embodiments of the present invention.

<Manufacture example 1> Manufacture of various peptides The following Examples 1-9 were manufactured by the solid-phase synthesis method (Fmoc method) like the method of Example 1 of Japanese translations of PCT publication No. 2005-538961 gazette. In the production of the peptide of each example, 1,3-diisopropylcarbodiimide / HOBt was used as a coupling reagent. The completion of the deprotection reaction and the peptide chain elongation reaction at each stage was confirmed by a ninhydrin test.
The peptide produced in each example was assayed by calculating the purity and analyzing the molecular weight by high performance liquid chromatography (conditions are detailed in each example). As a result, the purity of the partial peptides produced in each Example was 95% or more, and the results of molecular weight analysis also agreed well with the theoretical values. From these results, it was confirmed that each peptide was correctly produced.

[Example 1] Leu Gln Ser Asn Leu Thr Gly Phe Lys (SEQ ID NO: 3 or C1W)
HPLC [column: YMC-Pack ODS-AM (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 10% B 10 min; flow rate: 0.6 mL / min; detection 214 nm UV]
Retention time: 6.9 minutes (purity 98.9%)
MS (m / z) [ESI-MS]: 1007.8 (theoretical value: 1007.1)

[Example 2] Arg Gln Ser Asn Leu Thr Gly Phe Lys (SEQ ID NO: 4 or C1M (L / R))
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 10% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 7.2 minutes (purity 98.0%)
MS (m / z) [MALDI-TOF-MS]: 1050.8 (theoretical value: 1050.2)

[Example 3] Lys Gln Leu Glu Ile Leu Asn Phe Arg (SEQ ID NO: 5 or C2W)
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 15% B 20 min Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 11.6 minutes (purity 99.2%)
MS (m / z) [MALDI-TOF-MS]: 1159.7 (theoretical value: 1160.4
)

[Example 4] Lys Gln Leu Val Ile Leu Asn Phe Arg (SEQ ID NO: 6 or C2M (E / V))
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 20% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 6.9 minutes (purity 98.7%)
MS (m / z) [MALDI-TOF-MS]: 1130.6 (theoretical value: 1130.4)

[Example 5] Arg Arg Ser Asn Leu Thr Gly Phe Lys (SEQ ID NO: 7 or H1M (L / R))
HPLC column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 10% B 20 minutes; Flow rate: 1 mL / min; UV detection 214 nm]
Retention time: 6.5 minutes (purity 96.4%)
MS (m / z) [ESI-MS]: 1078.8 (theoretical value: 1078.2)

[Example 6] Leu Arg Ser Asn Leu Thr Gly Phe Lys (SEQ ID NO: 8 or H1W)
HPLC [column: YMC-Pack ODS-AM (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 10% B 20 min; flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 8.6 minutes (purity 98.1%)
MS (m / z) [ESI-MS]: 1035.2 (theoretical value: 1035.2)

[Example 7] Glu Gln Leu Glu Ile Leu Asn Phe Arg (SEQ ID NO: 9 or C2M (K / E))
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 20% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 9.2 minutes (purity 98.5%)
MS (m / z) [MALDI-TOF-MS]: 1162.0 (theoretical value: 1161.3)

[Example 8] Lys Gln Leu Ala Ile Leu Asn Phe Arg (SEQ ID NO: 10 or C2M (E / A))
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 15% B 20 min Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 11.0 minutes (purity 99.6%)
MS (m / z) [MALDI-TOF-MS]: 1102.3 (theoretical value 1103.0)

[Example 9] Lys Gln Leu Val Ile Leu Asn Phe Arg Lys Gln Leu Val Ile Leu Asn Phe Arg (SEQ ID NO: 15 or C2M (E / V) 2)
HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 20% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 10.8 minutes (purity 98.7%)
MS (m / z) [MALDI-TOF-MS]: 2243.2 (theoretical value: 2242.8)

<Manufacture example 2> Manufacture of various cyclic peptides The following Examples 10-11 were manufactured by the solid-phase synthesis method (Fmoc method) like the method of Example 1 of the Japanese translations of PCT publication No. 2005-538961 gazette. In the production of the peptide of each example, 1,3-diisopropylcarbodiimide / HOBt was used as a coupling reagent. Moreover, the completion | finish of the deprotection reaction of each step and the elongation reaction of a peptide chain was confirmed by the ninhydrin test. For the Cys in the peptide, Fmoc-Cys (Acm) -OH (N-α- (9-fluorenylmethoxycarbonyl) -S-acetaminomethyl-L-cysteine) is used, and the peptide is prepared using iodine. By cutting out from the resin, deprotection of the thiol group in the peptide and generation of a disulfide bond were performed.
The peptide produced in each example was assayed by calculating the purity and analyzing the molecular weight by high performance liquid chromatography (conditions are detailed in each example). As a result, the purity of the partial peptides produced in each Example was high, and the results of molecular weight analysis also agreed well with the theoretical values. From these results, it was confirmed that each peptide was correctly produced.

・ＨＰＬＣ［カラム：ＹＭＣ−Ｃ１８（１５０ Ｘ ４．６ ｍｍ）；溶媒系Ａ（０．０２％ ＴＦＡ／Ｈ₂Ｏ）、Ｂ（０．０２％ ＴＦＡ／ＣＨ₃ＣＮ）、２０％Ｂ ２０分；流速：１ｍＬ／分；検出２１４ｎｍのＵＶ］
保持時間：９．７分（純度８２．１％）
・ＭＳ（ｍ／ｚ）［ＭＡＬＤＩ−ＴＯＦ−ＭＳ］：１３３５．６（理論値１３３４．７） [Example 10]

HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 20% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 9.7 minutes (purity 82.1%)
MS (m / z) [MALDI-TOF-MS]: 1335.6 (theoretical value 1334.7)

・ＨＰＬＣ［カラム：ＹＭＣ−Ｃ１８（１５０ Ｘ ４．６ ｍｍ）；溶媒系Ａ（０．０２％ ＴＦＡ／Ｈ₂Ｏ）、Ｂ（０．０２％ ＴＦＡ／ＣＨ₃ＣＮ）、２０％Ｂ ２０分；流速：１ｍＬ／分；検出２１４ｎｍのＵＶ］
保持時間：１０．３分（純度７５．２％）
・ＭＳ（ｍ／ｚ）［ＭＡＬＤＩ−ＴＯＦ−ＭＳ］：２４４８．７（理論値２４４７．０）試験例１：ビオチン化ヒアルロン酸と各ペプチドとの結合活性比較実験
各ペプチド5 nmolをニトロセルロース膜にImmunoBlot（商標、Hoefer社製）を用いてイムノブロットした。10％ nonfat milk in phosphate-buffered saline (PBS) containing0.1％ Tween 20 (PBS-Tween)溶液にてブロッキングを４２℃にて１時間実施した。ヒアルロン酸（ニワトリ鶏冠由来：生化学工業株式会社製）はビオチン化して、2 mg/mLの濃度で準備した。ビオチン化の行程は井上らの報告（Inoue Y, Yoneda M, Zhao J, Miyaishi O, Ohno-Jinno A, Kataoka T, Isogai Z, Kimata K, Iwaki M, Zako M. Molecular cloning and characterization of chick SPACRCAN. J Biol Chem. 2006;281:10381-8.）に従った。ヒアルロン酸をPBS-Tween溶液にて500倍希釈して室温にて３０分間インキュベーションし、膜上のペプチドと結合させた。PBS-Tween溶液にて室温にて３０分間washした。HRP-conjugated streptavidin (GE Healthcare Bio-Sciences Corp., Piscataway, NJ)に
て室温にて３０分間インキュベーションした。PBS-Tween溶液にて室温にて３０分間washした。WESTERN LIGHTNING (商標、PerkinElmer Life Sciences Inc., Boston, MA) にて発光させ、Ｘ線フィルムに感光させて検出した。
C1Wにおける発光強度を１として実施例２〜１１で合成したペプチド又は環状ペプチドにおける発光強度と比較した結果を図１に示す。C2M(E/V)2、Cycle C2M(E/V)、Cycle C2M(E/V)2がそれぞれ67.7、58.1、62.7を示し、C1Wと比べて非常に高いヒアルロン酸結合能が認められた。 [Example 11]

HPLC [column: YMC-C18 (150 X 4.6 mm); solvent system A (0.02% TFA / H ₂ O), B (0.02% TFA / CH ₃ CN), 20% B 20 minutes Flow rate: 1 mL / min; detection 214 nm UV]
Retention time: 10.3 minutes (purity 75.2%)
MS (m / z) [MALDI-TOF-MS]: 2448.7 (theoretical value 2447.0) Test Example 1: Comparison of binding activity between biotinylated hyaluronic acid and each peptide 5 nmol of each peptide was added to a nitrocellulose membrane Immunoblotting was performed using ImmunoBlot (trademark, manufactured by Hoefer). Blocking was performed at 42 ° C. for 1 hour with a 10% nonfat milk in phosphate-buffered saline (PBS) containing 0.1% Tween 20 (PBS-Tween) solution. Hyaluronic acid (from chicken hen's crown: manufactured by Seikagaku Corporation) was biotinylated and prepared at a concentration of 2 mg / mL. The biotinylation process was reported by Inoue et al. (Inoue Y, Yoneda M, Zhao J, Miyaishi O, Ohno-Jinno A, Kataoka T, Isogai Z, Kimata K, Iwaki M, Zako M. Molecular cloning and characterization of chick SPACRCAN. J Biol Chem. 2006; 281: 10381-8.). Hyaluronic acid was diluted 500-fold with PBS-Tween solution and incubated at room temperature for 30 minutes to bind to the peptide on the membrane. Washed with PBS-Tween solution at room temperature for 30 minutes. Incubation was performed for 30 minutes at room temperature in HRP-conjugated streptavidin (GE Healthcare Bio-Sciences Corp., Piscataway, NJ). Washed with PBS-Tween solution at room temperature for 30 minutes. Light was detected by WESTERN LIGHTNING (Trademark, PerkinElmer Life Sciences Inc., Boston, Mass.) And detected by exposure to X-ray film.
FIG. 1 shows the result of comparison with the luminescence intensity of the peptides or cyclic peptides synthesized in Examples 2 to 11, where the luminescence intensity at C1W is 1. C2M (E / V) 2, Cycle C2M (E / V), and Cycle C2M (E / V) 2 showed 67.7, 58.1, and 62.7, respectively, and very high hyaluronic acid binding ability was recognized compared with C1W.

Test Example 2: Comparison experiment of binding activity between biotinylated heparan sulfate and each peptide The same operation as Test Example 1 was performed using heparan sulfate (derived from bovine kidney: manufactured by Seikagaku Corporation) instead of hyaluronic acid.
The result compared with the luminescence intensity in the peptide or cyclic peptide synthesized in Examples 2 to 11 with the luminescence intensity in C1W as 1 is shown in FIG. C2M (E / V) 2, Cycle C2M (E / V), and Cycle C2M (E / V) 2 showed 13.9, 4.9, and 25.8, respectively, indicating a very high heparan sulfate binding ability compared to C1W.

Test example 3: Comparison of binding activity between biotinylated chondroitin sulfate A and each peptide Using chondroitin sulfate A (derived from whale cartilage: Seikagaku Corporation) instead of hyaluronic acid, the same operation as in test example 1 was performed. It was.
The result compared with the luminescence intensity in the peptide or cyclic peptide synthesized in Examples 2 to 11 with the luminescence intensity in C1W as 1 is shown in FIG. C2M (E / V) 2, Cycle C2M (E / V), and Cycle C2M (E / V) 2 showed 105.3, 57.6, and 41.3 respectively, and very high chondroitin sulfate A binding ability was observed compared to C1W. .

Test Example 4: Comparison of binding activity between biotinylated chondroitin sulfate C and each peptide The same operation as in Test Example 1 was performed using chondroitin sulfate C (derived from shark cartilage: Seikagaku Corporation) instead of hyaluronic acid. It was.
The result compared with the luminescence intensity in the peptide or cyclic peptide synthesize | combined in Examples 2-11 by making the luminescence intensity in C1W into 1 is shown in FIG. C2M (E / V) 2, Cycle C2M (E / V), and Cycle C2M (E / V) 2 showed 171.7, 142.9, and 154.2, respectively. Very high chondroitin sulfate C-binding ability was observed compared to C1W. .

Test Example 5: Comparative experiment of hyaluronic acid efflux suppression ability Using a Cycle C2M (E / V) 2 aqueous solution adjusted to 1 μg / mL, write “H” on the cornea of pig eyes (purchased from Marusho Foods) with a brush. The pig eye was instilled with 10 μg / mL Fluorescein-HA. After 3 minutes, the pig eyes were washed every 3 minutes by dropping physiological saline. After washing 10 times, the pig eye's fluorescence state was photographed under the light irradiation condition with SFA-RB (BEX) (camera: Nikon D5100 (Nikon), lens: AF-S Micro NIKKOR 40mm 1: 2.8G) (Nikon Corporation). In addition, using a physiological saline instead of the Cycle C2M (E / V) 2 aqueous solution, “H” was written with a brush on the cornea of another pig eye, and the same operation was performed as a control.
A photograph of the control is shown in FIG. 5 (a), and a photograph of the test example is shown in FIG. 5 (b). Although the letter could not be recognized by the control, the letter “H” could be recognized from the pig eye of the test example, and Cycle C2M (E / V) 2 inhibited hyaluronic acid efflux from the cornea.

Test example 6: Comparative experiment of chondroitin sulfate C efflux suppression ability Using a Cycle C2M (E / V) 2 aqueous solution adjusted to 1 μg / mL, “C” with a brush on the cornea of pig eyes (purchased from Marusho Foods) The pig eye was instilled with 10 μg / mL Fluorescein-CS. After 3 minutes, the pig eyes were washed every 3 minutes by dropping physiological saline. After washing 10 times, the pig eye's fluorescence state was photographed under the light irradiation condition with SFA-RB (BEX) (camera: Nikon D5100 (Nikon), lens: AF-S Micro NIKKOR 40mm 1: 2.8G) (Nikon Corporation). Cycle C2M
Using a physiological saline instead of the (E / V) 2 aqueous solution, “C” was written with a brush on the cornea of another pig eye, and the same operation was performed as a control.
A photograph of the control is shown in FIG. 6 (a), and a photograph of the test example is shown in FIG. 6 (b). Although the letter could not be recognized by the control, the letter “C” could be recognized from the pig eye of the test example, and Cycle C2M (E / V) 2 inhibited chondroitin sulfate C efflux from the cornea.

Test Example 7: Comparative experiment of peeled retinal adhesion ability (1) Preparation of pig eye The pig eye (purchased from Marusho Foods) was incised into the eyeball along the ciliary body, and the anterior eye part and vitreous body were removed. Thereafter, the eye tissue was cut into an oval shape of 1 cm × 1.5 cm size on the posterior pole side of the eyeball. Further, the retina was detached from the eye tissue, and the generated water was wiped off with a Kimwipe.
(2) Comparison of peeled retinal adhesion ability Using the CycleC2M (E / V) 2 solution adjusted to 1 μg / mL, the solution was applied to the retina peeled off in Test Example 7, and the retina was adhered to the original eye tissue. After 1 minute, the above eye tissue is treated with wood (20cm x 2cm x
5mm) It was fixed with a needle at a position 1 cm away from one end of the long side. Paperweights (132 mm x 12 mm x 12 mm) were placed in a direction perpendicular to the wood at positions 1 cm away and 17 cm away from the position where the eye tissue of the wood was fixed. At this time, the paperweights crossed the wood at the center. In addition, wood and two paperweights were each fixed with rubber bands. Wood with fixed eye tissue and two paperweights is submerged in a 10L beaker containing 2L of PBS (-) solution. The time until the retina peeled away from the eye tissue by 3/4 or more or flowed away with water flow (time required for retinal detachment) was measured. In addition, another eye cell and a detached retina were adhered using physiological saline instead of the peptide aqueous solution, and the same operation was performed as a control.
FIG. 7 shows the time required for retinal detachment when using an aqueous peptide solution and a control. A significant increase in the time required for retinal detachment was observed with the aqueous peptide solution.

  The present invention provides a peptide having a high binding ability to glucosaminoglycans. The peptide of the present invention is extremely useful as an active ingredient for preventing or treating various diseases or as an adjuvant for improving the durability of glucosaminoglycan administered as an active ingredient, and is industrially applicable. have.

Claims (37)

Peptides represented by the following general formula (1) or general formula (2), derivatives thereof, pharmaceutically acceptable salts or solvates thereof (however, amino acid sequences represented by SEQ ID NOs: 3 to 6) Excluding peptides consisting of:
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.   The peptide represented by the general formula (1) or the general formula (2) according to claim 1, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the basic amino acid is Arg. His or Lys, the acidic amino acid is Asp or Glu, the branched amino acid is Leu, Ile or Val, the amide-containing amino acid is Asn or Gln, and the hydroxy-containing amino acid is Ser or Thr. Wherein the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp, or Tyr, and the sulfur-containing amino acid is Cys or Met, the peptide, its derivative, or a pharmaceutically acceptable product thereof Salts or solvates thereof. A peptide represented by the general formula (1) according to claim 1 or 2, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The peptide, derivative thereof, pharmaceutically acceptable salt or solvate thereof. A peptide represented by the general formula (2) according to claim 1 or 2, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The peptide, derivative thereof, pharmaceutically acceptable salt or solvate thereof.   The peptide of Claim 1 or 2 whose amino acid sequence is represented by sequence number 7-38, its derivative (s), their pharmaceutically acceptable salt, or those solvates.   The peptide of Claim 1 or 2 whose amino acid sequence is represented by SEQ ID NO: 15, 27, or 28, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof. A pharmaceutical comprising a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.   The pharmaceutical according to claim 7, wherein the basic amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, the branched amino acid is Leu, Ile or Val, and the amide-containing amino acid is , Asn or Gln, the hydroxy-containing amino acid is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid is Cys or The medicament, which is Met. A pharmaceutical comprising the peptide represented by the general formula (1) according to claim 7 or 8, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to claim 7 or 8. A pharmaceutical comprising the peptide represented by the general formula (2) according to claim 7 or 8, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to claim 7 or 8.   The pharmaceutical according to claim 7 or 8, comprising a peptide consisting of the amino acid sequence represented by SEQ ID NOs: 3 to 38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.   The pharmaceutical according to claim 7 or 8, comprising a peptide consisting of the amino acid sequence represented by SEQ ID NO: 15, 27 or 28, a derivative thereof, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient. .   The medicament according to any one of claims 7 to 12, which is used for prevention and / or treatment of an eye disease.   The medicament according to claim 13, wherein the eye disease is a retinal disease.   The medicament according to claim 14, wherein the retinal disease is retinal detachment, diabetic retinopathy or macular degeneration. (A) a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) A medicine containing glucosaminoglycan or a salt thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond. The pharmaceutical according to claim 16, wherein the basic amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, the branched amino acid is Leu, Ile or Val, and the amide-containing amino acid is , Asn or Gln, and the hydroxy-containing amino acid is
The aforementioned medicament, which is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid is Cys or Met. The component (A) is a peptide represented by the general formula (1) according to claim 16 or 17, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to claim 16 or 17. The component (A) is a peptide represented by the general formula (2) according to claim 16 or 17, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The medicine according to claim 16 or 17.   The medicine according to claim 16 or 17, wherein the component (A) is a peptide consisting of the amino acid sequence represented by SEQ ID NOs: 3 to 38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.   The component (A) is a peptide consisting of the amino acid sequence represented by SEQ ID NO: 15, 27 or 28, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 16 or 17. Medicine.   The medicine according to any one of claims 16 to 21, wherein component (B) is hyaluronic acid or a salt thereof.   The medicine according to any one of claims 16 to 22, which is used for prevention and / or treatment of an eye disease or a skin disease.   The medicament according to claim 23, wherein the eye disease is keratoconjunctival epithelial disorder.   The medicament according to claim 24, wherein the keratoconjunctival epithelial disorder is dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion or corneal ulcer.   24. The medicament according to claim 23, wherein the skin disease is sebum deficiency, progressive palmar keratoderma or atopic dermatitis. The form of the pharmaceutical composition which contains a component (A) and a component (B) in the same formulation, 16-16
26. The medicament according to any one of 26.   27. The medicament according to any one of claims 16 to 26, which is in the form of a kit formulation comprising component (A) and component (B) in separate formulations. (A) a peptide represented by the following general formula (1) or general formula (2), a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof;
(B) Cosmetics containing glucosaminoglycan or a salt thereof.
^{Y 1 -X 1 -X 2 -X 3} -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -Y 2 ( SEQ ID NO: 1)
(1)
^{Y 1 - (X 1 -X 2} -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9) 2 -Y 2 ( SEQ ID NO: 2)
(2)
[Where:
X ¹ independently represents a basic amino acid, an acidic amino acid or a branched amino acid;
X ² independently represents an amide-containing amino acid or a basic amino acid,
X ³ and X ⁶ each independently represent a branched amino acid or a hydroxy-containing amino acid,
X ⁴ independently represents a branched amino acid, an aliphatic amino acid, an amide-containing amino acid or an acidic amino acid,
X ⁵ independently represents a branched amino acid;
X ⁷ independently represents an aliphatic amino acid or an amide-containing amino acid,
X ⁸ independently represents an aromatic amino acid;
X ⁹ independently represents a basic amino acid;
Y ¹ and Y ² are not present at the same time or simultaneously represent a sulfur-containing amino acid, or
Y ¹ and Y ² simultaneously represent a sulfur-containing amino acid, and the amino acids Y ¹ and Y ² form an intramolecular bond.   30. The cosmetic according to claim 29, wherein the basic amino acid is Arg, His or Lys, the acidic amino acid is Asp or Glu, the branched amino acid is Leu, Ile or Val, and the amide-containing amino acid is , Asn or Gln, the hydroxy-containing amino acid is Ser or Thr, the aliphatic amino acid is Ala or Gly, the aromatic amino acid is Phe, Trp or Tyr, and the sulfur-containing amino acid is Cys or The cosmetic product, which is Met. The component (A) is a peptide represented by the general formula (1) according to claim 29 or 30, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (1),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The cosmetic according to claim 29 or 30. The component (A) is a peptide represented by the general formula (2) according to claim 29 or 30, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof,
In the general formula (2),
X ¹ and X ⁹ independently of each other represent Arg or Lys;
X ² and X ⁷ independently of each other represent Asn or Gln;
X ³ , X ⁴ , X ⁵ and X ⁶ independently of one another represent Leu, Ile or Val;
X ⁸ represents Phe, Trp or Tyr,
Y ¹ and Y ² do not exist at the same time, or indicate Cys at the same time, or
Y ¹ and Y ² simultaneously represent Cys and the amino acid forms a disulfide bond.
The cosmetic according to claim 29 or 30.   The cosmetic according to claim 29 or 30, wherein the component (A) is a peptide consisting of the amino acid sequence represented by SEQ ID NOs: 3 to 38, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.   The component (A) is a peptide comprising the amino acid sequence represented by SEQ ID NO: 15, 27, or 28, a derivative thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 29 or 30. Cosmetics.   The cosmetic according to any one of claims 29 to 34, wherein the component (B) is hyaluronic acid or a salt thereof.   36. The cosmetic product according to any one of claims 29 to 35, which is in the form of a composition comprising the component (A) and the component (B) in the same preparation.   36. A cosmetic product according to any one of claims 29 to 35, in the form of a kit comprising component (A) and component (B) in separate formulations.

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