Cyclic peptide and medicament, external preparation and cosmetic comprising cyclic peptide

Abstract

To provide a novel peptide with a high drug efficacy and strong effect, a medicament or external preparation comprising the same, specifically a prophylactic or therapeutic for dermatitis, rhinitis or alopecia, or a hair growth stimulant, a hair growing agent, an antipruritic or a skin-care product.SOLUTION: The present invention provides a cyclic peptide having a specific amino acid sequence or a derivative thereof or a pharmaceutically acceptable salt thereof, wherein the amino acid sequence does not have a peptide bond that is not between the amino acids constituting the amino acid sequence.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a cyclic peptide, and a medicine, an external preparation and a cosmetic preparation each containing the cyclic peptide. [Background technology]

[0002] BNP (brain natriuretic peptide) is a hormone synthesized and secreted by the heart (mainly the ventricles). BNP was isolated and identified from pig brains in 1988, and has since been known to be secreted by ventricular muscles in humans and other animals. When the load on the heart increases or the myocardium becomes hypertrophied, BNP is secreted and its blood concentration increases. In general, BNP has a diuretic effect, a vasodilatory effect, an inhibitory effect on renin and aldosterone secretion, an inhibitory effect on sympathetic nerves, and an inhibitory effect on hypertrophy, and is thought to be a hormone that acts to protect the myocardium from damage caused by cardiac stress.

[0003] Although the amino acids constituting BNP vary slightly depending on the individual species in which it is produced, it has been found that the structure of BNP has a common ring portion and tail portion (Non-Patent Documents 1-2). For example, wild-type human BNP is known to consist of 32 amino acid residues, and further, its fragments and derivatives have also been proposed (Patent Documents 1-6).

[0004] Currently, in Japan, BNP is not used as a therapeutic drug but is widely used in clinical settings as a biochemical marker for heart failure, while in the United States, it is also used as a drug (trade name: Natrecor (trademark)) to alleviate symptoms of heart failure. Recently, the use of topical agents containing BNP for the treatment of dermatitis, rhinitis, alopecia, etc., and for skin quality improvement agents has also been proposed (Patent Documents 7 to 9). [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Special Publication No. 2007-525213 [Patent Document 2] Special Publication No. 2008-509746 [Patent Document 3] International Publication No. 2008 / 032450 [Patent Document 4] U.S. Patent No. 6,028,055 [Patent Document 5] U.S. Pat. No. 5,114,923 [Patent Document 6] U.S. Patent No. 6,818,619 [Patent Document 7] International Publication No. 2011 / 010732 [Patent Document 8] International Publication No. 2011 / 024973 [Patent Document 9] International Publication No. 2012 / 099258 [Non-patent literature]

[0006] [Non-Patent Document 1] N. Akizukia, K. Kangawaa, N. Minaminob, H. Matsou, FEBS Letters 1991 280(2):357-362. [Non-Patent Document 2] Takei Y, Fukuzawa A, Itahara Y, Watanabe TX, Yoshizawa Kumagaye K, Nakajima K, Yasuda A, Smith MP, Duff DW, Olson KR. FEBS Lett. 1997 Sep 8;414(2):377-80. Summary of the Invention [Problem to be solved by the invention]

[0007] As mentioned above, BNP is considered to be a useful substance for the treatment of various diseases. However, in order to obtain a higher therapeutic effect, there is a demand for the development of substances with stronger efficacy and potency, as well as substances with faster and longer-lasting effects.

[0008] In addition, further improving the efficacy, duration of efficacy, and immediate effect is very meaningful from the viewpoint of reducing the number and frequency of necessary treatments, relieving the pain of patients and users, and improving the quality of life of users and their mental, physical, social, and intellectual satisfaction in daily life (QOL: quality of life). For example, dermatitis is often accompanied by symptoms such as itching, infiltration, and hot flashes in the affected area, and if these symptoms can be quickly alleviated, the pain of patients will be reduced. In addition, when using alopecia treatment agents, hair growth agents, and hair growth agents, if the treatment, hair growth, and hair growth effects are rapidly manifested, it is possible to improve the QOL of users.

[0009] The present inventors focused on these points and attempted to search for novel substances by referring to the structure of BNP. Therefore, an object of the present invention is to provide a novel peptide having strong medicinal effects and efficacy, and medicines and topical agents containing the same, particularly preventive or therapeutic agents for dermatitis, rhinitis, and alopecia, hair growth agents, hair restorers, antipruritic agents, cosmetics, skin care products, and the like. [Means for solving the problem]

[0010] It was previously believed that the tail portion of the peptide structure of BNP, which consists of a cyclic portion and a tail portion, plays at least a certain important role in the receptor binding and selectivity of wild-type BNP. However, the present inventors deliberately focused on the cyclic portion of the structure and conducted intensive research on cyclic peptides obtained by deleting the tail portion, resulting in completely new findings such as the high efficacy and medicinal effect of such cyclic peptides, the rapid onset of effect, and the increased durability of effect. As a result of further research, the present invention was completed. That is, the present invention relates to the following.

[0011] [1] Formula I: [ka] During the ceremony, X 1represents Gly, Val, Ala, Ser or Thr, X 2 indicates Arg, Gln or His, X 3 indicates Lys or Arg, X 4 represents Met, Leu or Ile, X 5 indicates Ile or Val, X 6 indicates Ser or Gly, X 7 indicates Ser or Ala, X 8 represents Ser, Gln, Val, Ala, Thr, Leu, Ile or Met, X 9 represents Ser, Val, Ala or Thr, X 10 indicates Gly or Arg, X 11 represents Leu, Met, Ile, Val or Ala, X 12 represents Gly, Ser or Ala, The line connecting the two Cys represents a disulfide bond. The amino acid sequence represented by The amino acid sequence does not have any peptide bonds other than those between the amino acids constituting the amino acid sequence. A cyclic peptide or a derivative thereof, or a pharma- ceutically acceptable salt thereof.

[0012] [2] X 2 indicates Arg, X 4 indicates Met, X 6 indicates Ser, X 7 represents Ser, and X 10 represents Gly, or a cyclic peptide or a derivative thereof, or a pharma- ceutically acceptable salt thereof, according to [1]. [3] The amino acid sequence is represented by the formula (Ia) to (Ie) [ka] [ka] [ka] [ka] [ka] In the formula, the line connecting the two Cys represents a disulfide bond. The cyclic peptide or its derivative or a pharma- ceutically acceptable salt thereof according to [1], wherein the cyclic peptide or its derivative is selected from the amino acid sequences represented by the following formula:

[0013] [4] The cyclic peptide or its derivative according to any one of [1] to [3], or a pharma- ceutically acceptable salt thereof, wherein the derivative is substituted with a substituent that can substitute for a hydrogen atom, a hydroxyl group, a carboxyl group, an amino group, or an imino group in the cyclic peptide. [5] A cyclic peptide or a derivative thereof, or a pharma- ceutically acceptable salt thereof, which is formed by deleting one to four amino acids in a cyclic peptide represented by any one of formulas (Ia) to (Ie) described in [3], or by substituting or adding other amino acids, and has a function equivalent to that of the cyclic peptide represented by each of the formulas. [6] An external preparation comprising one or more of the cyclic peptide and / or derivatives thereof according to any one of [1] to [5] and / or pharma- ceutically acceptable salts thereof. [7] The external preparation according to [6], which is a dermatitis treatment agent, a dermatitis prevention agent, an antipruritic agent, an anti-inflammatory agent, an epidermal regeneration promoter, a wound epithelialization promoter, or a material for skin care products.

[0014] [8] The external preparation according to [7], wherein the skin care product is for moisturizing, and / or for preventing and improving rough skin, and / or for treating sebum and acne, and / or for relieving irritation and anti-inflammation, and / or for whitening, and / or for preventing aging, and / or for preventing and relieving UV damage, and / or for slimming, and / or for cleansing the skin. [9] The topical preparation according to [6], which is a bath additive, a body cleanser, or a hair cleanser.

[10] The external preparation according to [6], which is an agent for treating alopecia, an agent for preventing alopecia, a hair growth agent and / or a hair regrowth agent.

[11] The external preparation according to [6], which is a rhinitis treatment agent and / or a rhinitis preventive agent.

[0015]

[12] The topical preparation according to [6], which is a cosmetic preparation.

[13] The external preparation according to any one of [6] to

[12] , wherein the dosage form is a solid, semisolid, powder, liquid, spray, ointment, cream, emulsion, gel, or patch.

[14] The topical preparation according to any one of [6] to

[13] , which is used as a medicine, a quasi-drug, or a cosmetic.

[15] Use of the cyclic peptide and / or its derivative and / or a pharma- ceutical acceptable salt thereof according to any one of [1] to [4] for the manufacture of an external preparation.

[0016]

[16] A method for using an external preparation, comprising applying the external preparation according to any one of [6] to

[14] to the skin and / or mucosa of a subject.

[17] The method for using the topical preparation described in

[16] , wherein the mucous membrane is the lips, oral cavity, nasal cavity, eye or vagina.

[18] A method for using the topical preparation according to

[16] , which is a method for treating and / or preventing dermatitis, a method for reducing or eliminating itching, a method for treating sores or ulcers caused by eczema or the like, or a skin care method.

[0017]

[19] A method for using the topical preparation described in

[16] , which is a method for treating and / or preventing alopecia and / or a method for promoting hair growth and / or a method for cultivating hair.

[20] A method for treating and / or preventing rhinitis using the topical preparation described in

[16] . [twenty one] A medicine comprising one or more of the cyclic peptides or derivatives thereof according to any one of [1] to [5], or pharma- ceutically acceptable salts thereof. [twenty two] The pharmaceutical according to

[21] , which is a therapeutic agent for hypertension, unstable angina, acute myocardial infarction, edema disease, renal failure, heart failure, immune disease, obesity, and metabolic syndrome. The cyclic peptides referred to here (hereinafter sometimes referred to as "BNP cyclic peptides", "B ring" or "B ring compounds") are derived from wild-type BNP as described above, and wild-type BNP includes not only those derived from humans but also those derived from monkeys, pigs, birds and rats. Therefore, B ring compounds include not only those derived from humans but also those derived from monkeys, pigs, birds and rats. Effect of the Invention

[0018] According to the present invention, a novel cyclic peptide and a composition containing the same can be provided. Such a composition can be used as an external preparation for preventing or treating dermatitis, rhinitis, and alopecia, as well as a hair growth agent, hair restorer, and antipruritic agent, and can be provided as a medicine, quasi-drug, skin care product, cosmetic, etc. In the present invention, the term "external preparation" refers to an agent that is applied to the skin or mucous membrane, and is not limited to applications such as medicine, quasi-drug, skin care product, and cosmetic.

[0019] The topical preparation of the present invention is generally more effective against dermatitis than conventional topical steroid preparations, and has an excellent immediate effect, with symptoms generally beginning to improve within 3 minutes, and its effect is also strong and sustained, with a long remission period. Furthermore, when the topical preparation of the present invention is applied to the skin or mucous membrane of a subject suffering from dermatitis, it can improve the symptoms of dermatitis while rapidly alleviating or eliminating various perceptible symptoms and conditions such as itching, pain (ache), heat, tightness, infiltration, erythema, etc., which are caused or may be caused by dermatitis.

[0020] Furthermore, the topical preparation of the present invention not only exerts a moisturizing effect at the application site, but also exerts an effect of smoothing the texture of the application site when the stratum corneum is present at the application site, thereby resulting in smoothing the texture, improving dry skin and rough skin, making the skin soft and moist, making wrinkles shallower and less noticeable, and even improving rough lips.

[0021] In addition, when the topical agent of the present invention is applied to the site of hair loss or hair growth, it has the effect of preventing hair loss at the application site and promoting hair growth or hair growth.In this case, the hair that grows tends to be terminal hair and tends to be non-white hair.In addition, these effects appear relatively early compared to other active ingredients used in conventional alopecia treatments, such as BNP, and the effect obtained is also remarkable.

[0022] Furthermore, the topical preparation of the present invention has an immediate effect on rhinitis, is highly effective, and has a long-lasting effect with a long remission period.

[0023] In addition, since the cyclic peptide of the present invention is a peptide having a common portion in its structure with BNP, a hormone originally provided in the body, there is little concern about side effects, and as long as the amount used is appropriate or when applied externally to the skin, the effect on hemodynamics is considered to be minor, so it can be administered long-term to patients who require administration over a long period of time, such as patients with chronic dermatitis. Furthermore, the external preparation of the present invention does not cause irritation when applied externally, and can be safely applied to the face, neck, etc. of children and women as well as to patients with sensitive skin.

[0024] In addition, the reason why the cyclic peptide of the present invention has superior efficacy and potency compared with wild-type BNP is not necessarily clear, but according to the in silico analysis by the present inventors, it is suggested that the cyclic peptide of the present invention is more easily bound to NPR-A receptor (GC-A) and more strongly bound to it compared with wild-type BNP, and from this, it is inferred that the cyclic peptide has excellent efficacy and potency, especially its immediate effect.In addition, as mentioned above, B-ring compounds are not only derived from humans, but also from different animals, for example, from monkeys, pigs, birds, and rats, and it has been confirmed that they have similar structures, and it is strongly inferred that all B-rings have the same effects as B-ring compounds derived from humans, based on the results of structural analysis described below. [Brief description of the drawings]

[0025] [Figure 1] FIG. 1 shows the results of applying a BNP cyclic peptide (A) and a gel formulation (B) to the left and right sides of a subject with large wrinkles on the face. [Diagram 2] FIG. 1 shows the effects of a B-ring gel preparation and a BNP gel preparation before and after application to patients with female pattern alopecia and pityriasis alopecia. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention will be described in detail below based on preferred embodiments.

[0027] 1. Cyclic peptides, their derivatives and pharma- ceutically acceptable salts First, the cyclic peptide of the present invention, its derivatives, and pharma- ceutically acceptable salts thereof will be explained. The cyclic peptides of the present invention have the formula I: [ka] (SEQ ID NO:1)

[0028] During the ceremony, X 1 represents Gly, Val, Ala, Ser or Thr, X 2 indicates Arg, Gln or His, X 3 indicates Lys or Arg, X 4 represents Met, Leu or Ile, X 5 indicates Ile or Val, X 6 indicates Ser or Gly, X 7 indicates Ser or Ala, X 8 represents Ser, Gln, Val, Ala, Thr, Leu, Ile or Met, X 9 represents Ser, Val, Ala or Thr, X 10 indicates Gly or Arg, X 11 represents Leu, Met, Ile, Val or Ala, X 12 represents Gly, Ser or Ala, The line connecting the two Cys represents a disulfide bond. The amino acid sequence represented by The amino acid sequence is a cyclic peptide that does not have any peptide bonds other than between the amino acids that make up the amino acid sequence. Like the conventionally known BNP, these cyclic peptides bind to the receptor NPR-A (also known as GC-A) which has a guanylate cyclase domain and promote the production of cyclic guanosine monophosphate (cGMP), and are thought to have effects such as diuretic action, vasodilatory action, inhibition of renin and aldosterone secretion, sympathetic nerve suppression, and inhibition of hypertrophy. However, compared to BNP, they have superior pharmacological effects and efficacy, especially superior immediate action.

[0029] As described below, the cyclic peptide can be used as a component of external preparations such as dermatitis treatment / prevention agents, rhinitis treatment / prevention agents, alopecia treatment / prevention agents, hair growth agents, hair growth agents, and antipruritic agents, and can also be used as a material for skin care products, quasi-drugs, and cosmetics. Furthermore, the cyclic peptide can be used as a substitute for BNP in medicines that utilize the activity of BNP, such as medicines for hypertension, unstable angina, acute myocardial infarction, edema diseases, renal failure, heart failure, immune diseases, obesity, and metabolic syndrome.

[0030] In another embodiment of the present invention, the cyclic peptide of the present invention is represented by the formula (I), 1 ~X 12 However, the following (1) to (12): (1)X 1 represents Gly, Val, Ala, Ser or Thr; (2)X 2 represents Arg, Gln or His; (3) X 3 represents Lys or Arg; (4) X 4 represents Met, Leu or Ile; (5)X 5 indicates Ile or Val, (6)X 6 represents Ser or Gly; (7)X 7 represents Ser or Ala, (8)X 8represents Ser, Gln, Val, Ala, Thr, Leu, Ile or Met; (9)X 9 represents Ser, Val, Ala or Thr; (10)X 10 represents Gly or Arg; (11)X 11 represents Leu, Met, Ile, Val or Ala, and (12)X 12 represents Gly, Ser or Ala; It may be one or more selected from the group consisting of: The cyclic peptide of the present invention is also a cyclic peptide represented by the formula (I) above, 2 indicates Arg, and X 4 indicates Met, and X 6 indicates Ser, and X 7 indicates Ser and / or X 10 A cyclic peptide (SEQ ID NO: 2) in which represents Gly is preferred.

[0031] Furthermore, in another embodiment of the present invention, the cyclic peptide of the present invention may have an amino acid sequence represented by formula (I) selected from SEQ ID NOs: 3 to 8 and SEQ ID NOs: 16 to 75.

[0032] Furthermore, the cyclic peptide of the present invention is such that the amino acid sequence represented by formula (I) is any one of the following formulas (Ia) to (Ie): [ka] (SEQ ID NO:3) [ka] (SEQ ID NO:4) [ka] (SEQ ID NO:5) [ka] (SEQ ID NO:6) [ka] (SEQ ID NO:7) In the formula, the line connecting the two Cys represents a disulfide bond. It is preferable that the amino acid sequence is selected from the amino acid sequences represented by:

[0033] The amino acid sequences represented by the formulas (Ia) to (Ie) are the cyclic portions of human BNP (formula (Ia)), porcine BNP (formula (Ib)), rat BNP (formula (Ic)), rabbit BNP (formula (Id)) and mouse BNP (formula (Ie)), respectively. Therefore, a cyclic peptide having such an amino acid sequence can more reliably exert the above-mentioned effects. The porcine BNP cyclic peptide was synthesized from avian (SEQ ID NO: 8, Cys-Phe-Gly-Arg-Arg-Ile-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Met-Gly-Cys, in which the first and 17th Cys form a disulfide bond), bovine (SEQ ID NO: 9, Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys, in which the first and 17th Cys form a disulfide bond), feline (SEQ ID NO: 10, Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys, in which the first and 17th Cys form a disulfide bond), and feline (SEQ ID NO: 11, Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys, in which the first and 17th Cys form a disulfide bond). ly-Cys, where the first Cys and the 17th Cys are disulfide bonded), dog (SEQ ID NO: 11, Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys, where the first Cys and the 17th Cys are disulfide bonded), and sheep (SEQ ID NO: 12, Cys-Phe-Gly-Arg-Arg-Leu-Asp-Arg-Ile-Gly-Ser-Leu-Ser-Gly-Leu-Gly-Cys, where the first Cys and the 17th Cys are disulfide bonded), so the BNP cyclic peptides derived from these organisms also have the same effect as the present invention. In particular, among the above, it is preferable that the amino acid sequence represented by formula (I) is the amino acid sequence represented by formula (Ia). In another embodiment of the present invention, the cyclic peptide may be any of the cyclic peptides represented by SEQ ID NOs: 16 to 75.

[0034] The cyclic peptide of the present invention includes a derivative of the above-mentioned cyclic peptide. Such a derivative can be used as an active substance as it is, or can be used as a prodrug.

[0035] The derivatives of the present invention can be obtained by adding (modifying) a known substituent to a specific group of an amino acid in a cyclic peptide, such as a hydrogen atom, a hydroxyl group, a carboxyl group, an amino group, an imino group, etc., or by substituting a known substitutable substituent. Modifications include, but are not limited to, chemical modifications such as sugar chain addition, acetylation, phosphorylation, and lipid addition to an amino acid in a cyclic peptide.

[0036] In addition, the addition (modification) or substitution to the group of the amino acid in the cyclic peptide may occur simultaneously with one or more groups, or more than one group. Note that such a substituent is not particularly limited as long as it can be substituted for the above-mentioned group, and known substituents can be used, and it goes without saying that protecting groups such as BOC are also included.

[0037] Furthermore, the cyclic peptide of the present invention also includes a mutant of the cyclic peptide. That is, the mutant of the present invention can be obtained by deleting an amino acid in the cyclic peptide, or by substituting or adding another amino acid. The number of amino acids to be deleted, or to be substituted or added by another amino acid is 4 or less, more preferably 3 or less, even more preferably 2 or less, and particularly preferably 1 or less. It goes without saying that the deletion of an amino acid in the cyclic peptide and the substitution or addition by another amino acid may occur independently and simultaneously.

[0038] In addition, the amino acids that may be substituted with other amino acids can be exemplified as follows in the case of human BNP (formula (Ia)), but are not limited thereto. The third amino acid from the left, Gly, may be substituted with either Val, Ala, Ser, or Thr. The fourth amino acid from the left, Arg, may be substituted with either Gln or His. The fifth amino acid from the left, Lys, may be substituted with Arg. The sixth amino acid from the left, Met, may be substituted with either Leu or Ile. The ninth amino acid from the left, Ile, may be substituted with Val. The twelfth amino acid from the left, Ser, may be substituted with either Gln, Val, Ala, Thr, Leu, Ile, or Met. The thirteenth amino acid from the left, Ser, may be substituted with either Val, Ala, or Thr. The fourteenth amino acid from the left, Gly, may be substituted with either Arg. The fifteenth amino acid from the left, Leu, may be substituted with either Met, Ile, Val, or Ala. The 16th amino acid from the left, Gly, may be substituted with either Ser or Ala. Examples of amino acids that can be substituted in the cyclic peptide of the present invention are summarized in Table 32, but are not limited thereto.

[0039] In addition, examples of cyclic peptides in which one amino acid is substituted include, but are not limited to, SEQ ID NOs: 16 to 44, etc. In addition, examples of cyclic peptides in which two amino acids are substituted include, but are not limited to, SEQ ID NOs: 45 to 58, etc. In addition, examples of cyclic peptides in which three amino acids are substituted include, but are not limited to, SEQ ID NOs: 59 to 70, etc. In addition, examples of cyclic peptides in which four amino acids are substituted include, but are not limited to, SEQ ID NOs: 71 to 75, etc. In addition, it goes without saying that five or more amino acids can be substituted by appropriately combining the above-mentioned amino acids.

[0040] One to several amino acids can be deleted in the same manner as the amino acids that can be substituted with other amino acids described above.

[0041] Furthermore, the number of amino acids to be deleted or substituted or added with other amino acids may be 80% homologous to the cyclic peptide of the present invention, and preferably 90% homologous.

[0042] Furthermore, the present invention may be the above-mentioned mutant and also its derivative. As long as it has the effect of the present invention, any mutant or its derivative is included in the cyclic peptide of the present invention. In another embodiment, it may have at least BNP activity. In addition, for the purpose of improving the activity of the cyclic peptide of the present invention, sustaining the effect of the present invention, and / or increasing the storage stability of the cyclic peptide of the present invention, the cyclic peptide of the present invention or the amino acids constituting it can be appropriately modified. For example, chemical modification of the amino acids of the cyclic peptide of the present invention can be performed, some amino acids constituting the cyclic peptide can be deleted, replaced with other amino acids, and / or new amino acids can be added.

[0043] For example, the C-terminal group of one Cys in the cyclic peptide is replaced with -COOH, 1 , -CONHR 1 or -CONR 12 and / or the N-terminal group of the other Cys of the cyclic peptide is replaced with NH2 to -NHC(O)R 1 or -N(C(O)R 1 )2, where R 1 is independently a branched or linear hydrocarbon group having 1 to 20 carbon atoms, an alkylene glycol chain, or a sugar chain at each occurrence. 1 The number of carbon atoms is preferably 1 to 10, more preferably 1 to 5, and further preferably 1 to 2.

[0044] In addition, the cyclic peptide or derivative of the present invention may include, but is not limited to, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; as well as aluminum salts and ammonium salts. Suitable examples of salts with organic bases include salts with alkylamines such as trimethylamine and triethylamine; salts with heterocyclic amines such as pyridine and picoline; salts with alkanolamines such as ethanolamine, diethanolamine, and triethanolamine; salts with cycloalkylamines such as cyclohexylamine and dicyclohexylamine; and salts with alkylenediamine derivatives such as N,N'-dibenzylethylenediamine. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Suitable examples of salts with organic acids include salts with monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, and propionic acid; salts with polycarboxylic acids such as fumaric acid, oxalic acid, and maleic acid; salts with oxycarboxylic acids such as tartaric acid, citric acid, succinic acid, and malic acid; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and salts with benzoic acid. Suitable examples of salts with neutral amino acids include salts with glycine, valine, and leucine, suitable examples of salts with basic amino acids include salts with arginine, lysine, and ornithine, and suitable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

[0045] Among the above, a cyclic peptide consisting of an amino acid sequence represented by formula (I) or a pharma- ceutically acceptable salt thereof is preferred. That is, the amino acid sequence represented by formula (I) is preferably unsubstituted.

[0046] The method for producing the cyclic peptide of the present invention, its derivatives, and pharma- ceutical acceptable salts thereof is not particularly limited, and for example, known chemical synthesis methods or genetic engineering synthesis methods can be used.

[0047] When the amino acid sequence is synthesized by chemical synthesis, any chemical synthesis method may be used, and the peptide may be synthesized by a known peptide synthesis method, such as solid-phase synthesis or liquid-phase synthesis. A commercially available peptide synthesizer (e.g., Shimadzu Corporation's PSSM-8) may also be used for the synthesis.

[0048] Furthermore, disulfide bonds in an amino acid sequence can be formed by, but are not limited to, for example, DMSO oxidation method, iodine oxidation method, etc. In this case, intramolecular disulfide bonds can be formed by treating a free sulfhydryl group or a sulfhydryl group protected by a protecting group with DMSO or iodine (I2), resulting in a cyclic peptide.

[0049] Examples of the protecting group include 4-methylbenzyl group (Bzl(4Me)), trityl group (Trt), tert-butyl group, N-(acetyl)aminomethyl group (Acm), etc. Deprotection can be carried out by an appropriate treatment corresponding to the protecting group, for example, by treating with a strong acid for the 4-methylbenzyl group and with iodine for the N-(acetyl)aminomethyl group.

[0050] Next, the cyclic peptide is derivatized as necessary to obtain a derivative. The derivatization can be performed by a known method. Alternatively, a substituent may be introduced in advance into the amino acid that constitutes the cyclic peptide to produce a derivative of the cyclic peptide at the same time as the peptide is synthesized.

[0051] Then, if necessary, a pharma- ceutically acceptable salt is prepared by carrying out a salt exchange of the cyclic peptide or derivative, for example, by contacting the cyclic peptide or derivative with a desired acid or base.

[0052] On the other hand, when the peptide is synthesized by genetic engineering, it can be synthesized by a known method, for example, a method described in Sambrook J. et al., Molecular Cloning, A Laboratory Manual (4th edition) (Cold Spring Harbor Laboratory Press (2012)). For example, first, a DNA fragment encoding the amino acid sequence represented by formula (I) is prepared. For example, in the case of a DNA fragment encoding the amino acid sequence represented by formula (Ia), the DNA fragment can be prepared by amplifying the DNA fragment by PCR using a primer designed to synthesize a specific DNA region, using a vector containing the full-length human BNP gene as a template. The DNA fragment may also be chemically synthesized.

[0053] Next, the amplified DNA fragment is ligated to an appropriate vector to obtain a recombinant vector for protein expression. Next, the recombinant vector for protein expression is introduced into target cells, and the cells that have taken up the vector are selected. Finally, the protein produced from the cells (the protein consisting of the amino acid sequence represented by formula (I)) is collected. Disulfide bond formation, derivatization, and salt formation in the recovered protein can be carried out as described above.

[0054] Whether or not the desired compound such as a cyclic peptide has been obtained can be confirmed by known techniques such as reverse phase HPLC and mass spectrometry. Furthermore, the presence or absence of BNP activity of the obtained compound can be easily confirmed by known means, for example, by testing cGMP production activity in NPR-A receptor expressing cells.

[0055] 2. Topical agents Next, the topical agent of the present invention will be described. The topical agent of the present invention comprises one or more of the above-mentioned cyclic peptides and / or their derivatives and / or their pharma- ceutically acceptable salts. When using two or more cyclic peptides, there is no particular upper limit to the types of cyclic peptides to be mixed, but from the viewpoint of preparation cost and convenience, about 2 to 3 types are preferred. For example, SEQ ID NO: 19, 29, 33, 36, 39 and 43 can be mentioned, but they are not limited thereto as long as they do not impair the effects of the present invention, and these cyclic peptides can be appropriately combined according to the application target, etc.

[0056] 2.1 Application The topical preparation of the present invention can be used for, but is not limited to, the following applications, and in each case, it exhibits unprecedentedly remarkable effects. The topical preparation of the present invention is not particularly limited in any application, and can be used as a medicine, quasi-drug, and / or cosmetic depending on its efficacy and efficacy.

[0057] Each application will be described in detail below. (1) Dermatitis treatment and prevention agents The topical preparation of the present invention can be an agent for treating dermatitis and / or an agent for preventing dermatitis.

[0058] When applied to the skin or mucosa of a subject suffering from dermatitis, the topical preparation of the present invention can improve the symptoms of dermatitis while rapidly alleviating or eliminating various perceptible symptoms and conditions such as itching, pain (ache), heat, tightness, erythema, infiltration, papule, lichenification, crust, exudation, dry skin, etc., which are caused or may be caused by dermatitis. In addition, the topical preparation of the present invention does not cause irritation at the application site.

[0059] And, such an effect of the external preparation containing the cyclic peptide of the present invention is more rapid and lasts longer than the effect of the external preparation containing BNP with tail.The reason of the advantageous effect of the cyclic peptide compared to BNP is not clear, but it is considered that the cyclic peptide of the present invention has a structure that is more advantageous for binding to its receptor, the NPR-A receptor, compared to BNP, and therefore it can bind to the NPR-A receptor near the affected area more quickly and its binding time is longer.In addition, it is considered that by binding to the NPR-A receptor near the affected area relatively quickly, the cyclic peptide can be prevented from diffusing outside the affected area by blood flow, etc., and the cyclic peptide can be kept near the affected area for a relatively long time.

[0060] In addition, the topical preparation of the present invention not only suppresses or prevents inflammation of dermatitis, but also restores or maintains the barrier function of the skin. Here, the barrier function of the skin has a function of preventing stimuli from the external environment and the intrusion of bacteria and the like into the skin, and a moisturizing function, and the progress and worsening of inflammation can be prevented by restoring the barrier function with the topical preparation. Note that the barrier function of the skin is greatly influenced by the alignment state of the keratinocytes of the stratum corneum, that is, the texture state and the moisturizing state, and the topical preparation of the present invention has the effect of smoothing the texture and moisturizing the skin, so that the topical preparation also has the effect of restoring and maintaining the barrier function of the skin.

[0061] The topical preparation of the present invention is also effective against skin conditions such as comedones, commonly known as acne, red papules, pustules, cysts and nodules.

[0062] In addition, the rapid alleviation or disappearance of perceptible symptoms and conditions reduces the burden on the subject (patient), improves the patient's QOL, and prevents the patient from touching or scratching the affected area, which may damage the affected area, due to concerns about itching or pain. The alleviation or disappearance effect of the topical preparation of the present invention on perceptible symptoms and conditions generally occurs within 10 minutes, preferably within 5 minutes, and more preferably within 3 minutes after application.

[0063] In addition, the topical preparation of the present invention can treat dermatitis resulting from steroid dermatitis, and dermatitis that cannot be treated with other general drugs for treating dermatitis such as steroids and tacrolimus, for example, dermatitis for which satisfactory therapeutic effects are not obtained, for which there is resistance to those preparations, or for which use is not suitable or desirable, etc. Furthermore, in the case of topical steroid preparations that have been widely used up until now, there has been a major problem that, when topical application is discontinued, the severity immediately returns to the level before topical application, or a rebound phenomenon occurs, making the condition worse than before topical application, but the topical preparation of the present invention does not have such a problem of rebound phenomenon.

[0064] Dermatitis is generally a disease that causes inflammation on the skin or mucous membrane. Dermatitis is usually accompanied by one or more symptoms selected from the group consisting of acute eczema symptoms such as erythema, infiltrative erythema, papules, vesicles, pustules, infiltration, crusts, and desquamation, chronic eczema symptoms such as lichenification and pigmentation, and scales, crusts, scratches, scratches, prurigo nodules, erosions, edema, oozing sensation, and scaly skin.

[0065] Here, dermatitis is not particularly limited as long as it is a disease accompanied by inflammation on the skin or mucous membrane, and examples thereof include eczema such as chronic eczema, dyshidrotic eczema, and pediatric dry eczema, atopic dermatitis; contact dermatitis such as allergic contact dermatitis and primary irritant contact dermatitis; seborrheic dermatitis; asteatotic dermatitis; autosensitization dermatitis; stasis dermatitis; urticaria such as allergic urticaria (e.g., food urticaria, drug urticaria) and non-allergic urticaria (e.g., physical urticaria, solar urticaria, cholinergic urticaria); insect bites; drug rash; psoriasis vulgaris, dropsy, etc. Examples of skin diseases that may be caused by skin rash include psoriasis such as psoriasis erythroderma, pustular psoriasis, and psoriatic arthropathy; prurigo such as chronic prurigo, acute prurigo, prurigo of pregnancy, and prurigo nodularis; rosacea; rosacea-like dermatitis; cutaneous vasculitis such as cutaneous allergic vasculitis; cutaneous pruritus such as generalized pruritus, localized pruritus, senile pruritus, and pruritus of pregnancy; photodermatitis; erythroderma; nummular dermatitis; localized excoriation dermatitis; perioral dermatitis; pimples; porokeratosis; lichen planus, dyshidrotic eczema, dyshidrosis, miliaria, and acne vulgaris. The topical preparation of the present invention can be used to treat and prevent any of these diseases.

[0066] The topical preparation of the present invention is particularly effective against eczema, atopic dermatitis, contact dermatitis, seborrheic dermatitis, insect bites, allergic or non-allergic urticaria, and psoriasis, preferably against eczema, atopic dermatitis, contact dermatitis, and insect bites, and more preferably against eczema and atopic dermatitis. Therefore, the topical preparation of the present invention can be used for the purpose of treating or preventing at least one or more types of dermatitis selected from the above group.

[0067] (2) Cosmetics or skin care ingredients The topical preparation of the present invention can be a cosmetic or skin care product material. When the topical agent of the present invention is applied to the skin and / or mucous membrane, it moisturizes the application site, exerts a moisturizing effect, and prevents dryness and rough skin. When the stratum corneum is present at the application site, it exerts an effect of smoothing the texture of the application site. In addition, it imparts and maintains appropriate elasticity and flexibility to the skin and mucous membrane, softens the skin, and gives firmness and tightens the skin and mucous membrane. In addition, wrinkles and sagging, including fine and large wrinkles, are improved at the application site, and dullness and blemishes are made less noticeable. In addition, since dullness and blemishes are made less noticeable, a whitening effect is obtained as a result.

[0068] As a result, the topical preparation of the present invention can be used for the purpose of maintaining or improving the condition of the skin and / or mucosa, without being particularly limited thereto, for example, preventing the occurrence, progression or improvement of dry skin, rough skin, sensitive skin, chapped lips, sagging, fine lines and large lines, as well as for at least one purpose selected from the group consisting of maintaining the condition of the skin or mucosa, anti-aging and whitening, or for the purpose of obtaining at least one effect selected from the effects described above. In this specification, rough skin includes heat rash, chilblains, cracks, chapped skin, acne, diaper rash, sores, chapped skin, and razor burn.

[0069] Specific uses of the topical preparation of the present invention as a cosmetic or skin care product material are not particularly limited, but include, for example, lotion, milky lotion, serum, cream, cold cream, gel, mask, pack, powder, hand soap, perfume, deodorant, makeup cosmetics such as foundation, face powder, eye shadow, eyeliner, mascara, eyebrow, blush, makeup base, lipstick, lip balm, nail color, and other makeup cosmetics, hair cosmetics such as shampoo, rinse, conditioner, hair color, hair tonic, setting agent, permanent agent, and other hair cosmetics, body cleansers such as facial cleanser, cleanser, body soap, and other body care products such as body powder, aftershave lotion, pre-shave lotion, and bath additives (bath additives).

[0070] The above-mentioned effects of the topical preparation of the present invention are exerted rapidly, and although they vary depending on the type of effect, they are generally exerted within 10 minutes, preferably within 5 minutes, and more preferably within 3 minutes after application. Furthermore, the above-mentioned effects of the topical preparation of the present invention last for a relatively long time, and although this varies depending on the type of effect, it generally lasts for 4 hours or more after the effect is exerted, preferably 8 hours or more, and more preferably 24 hours or more.

[0071] (3) Antipruritic The topical preparation of the present invention can be an antipruritic agent. As described above, the topical preparation of the present invention is suitable as an antipruritic agent because it rapidly exerts an excellent antipruritic effect at the application site when applied to the skin or mucous membrane. Moreover, the antipruritic effect of the topical agent of the present invention as described above generally appears within 10 minutes, preferably within 5 minutes, and more preferably within 3 minutes after application.

[0072] (4) Alopecia treatments, alopecia prevention agents, hair restorers and hair growth agents Furthermore, the topical preparation of the present invention can be an agent for treating alopecia, an agent for preventing alopecia, a hair growth agent and / or a hair regrowth agent. When the topical agent of the present invention is applied to a site such as hair loss site or hair growth site, it has the effect of preventing hair loss at the application site and promoting hair growth or hair growth.In addition, at the application site, it has the effect of hair nourishment, hair growth promotion, and thinning hair improvement and prevention.In this case, the hair that grows tends to be hard hair and not gray hair.In addition, these effects appear relatively early compared to other active ingredients used in conventional alopecia treatment agents, such as BNP, and the effect obtained is also remarkable.

[0073] In addition, the topical agent of the present invention has the effect of improving and preventing dermatitis as described above.Therefore, it can improve or prevent the inflammation of the skin associated with alopecia.This effect is particularly advantageous when alopecia is aggravated due to the condition of the skin at the application site such as scalp.

[0074] Furthermore, when the topical agent of the present invention is applied to the skin as described above, it exerts a moisturizing effect and a texture-conditioning effect at the application site. It can eliminate dandruff and itching and suppress their occurrence, and also moisturize the hair and scalp, improve and prevent dryness, and keep the scalp and hair healthy. It can also improve seborrheic conditions.

[0075] In addition, the topical agent of the present invention has the effect of alleviating and eliminating perceptible symptoms and conditions as described above.This reduces the burden on the subject (patient) and improves the QOL of the patient.Furthermore, it can prevent the patient from touching or scratching the affected area, which is a cause of injury to the affected area, because of itching or pain, and thus can prevent the deterioration of the skin condition that causes alopecia.

[0076] When the topical preparation of the present invention is used as an agent for treating or preventing alopecia, the applicable alopecia is not particularly limited, and examples thereof include the following alopecia, and the preparation can be used for the purpose of treating or preventing one or more of these alopecia.

[0077] (Acquired alopecia) (i) Alopecia without scarring or skin lesions (alopecia areata, androgenetic alopecia, seborrheic alopecia, pityriasis grisea, female pattern alopecia, pregnancy-related alopecia, malignant alopecia, senile alopecia, alopecia totalis, alopecia multiplex, alopecia serpiginosa, drug-induced alopecia, chemotherapy-induced alopecia and alopecia due to radiation exposure, traumatic or mechanical alopecia, alopecia associated with nutritional or metabolic disorders, alopecia associated with endocrine abnormalities, telogen effluvium (postpartum alopecia, post-hyperthermia))

[0078] (ii) Alopecia due to skin lesions or diseased skin (alopecia due to infection, alopecia due to tumor, alopecia due to inflammation) (iii) Cicatricial alopecia (hair loss due to skin infections or inflammatory cell infiltration)

[0079] (Congenital alopecia) Diffuse alopecia, congenital atrichosis, alopecia in hereditary syndromes, focal alopecia, nevus, aplasia cutis, congenital triangular alopecia

[0080] Among the above, the topical preparation of the present invention is particularly effective against acquired alopecia, preferably against alopecia without scar or skin lesion, more preferably against alopecia areata, androgenetic alopecia, seborrheic alopecia, pityriasis grisea, female pattern alopecia, pregnancy alopecia, malignant alopecia, senile alopecia, alopecia totalis, alopecia multiplex, serpentine alopecia, drug-induced alopecia, cancer chemotherapy drug-induced alopecia and radiation exposure-induced alopecia, traumatic / mechanical alopecia, alopecia associated with nutritional disorder / metabolic disorder, alopecia associated with endocrine abnormality, and telogen effluvium.Therefore, the topical preparation of the present invention can be used for the purpose of treating or preventing at least one or more types of alopecia selected from the above group.

[0081] (5) Rhinitis treatment and / or prevention agent Furthermore, the topical preparation of the present invention can be an agent for treating rhinitis and / or an agent for preventing rhinitis. Rhinitis is a disease caused by inflammation of the mucous membrane of the nasal cavity and / or paranasal sinuses, and causes symptoms such as nasal congestion, rhinorrhea, sudden repeated sneezing, as well as itching, etc. In the present invention, "rhinitis" includes not only rhinitis accompanied by inflammation of the nasal mucous membrane in the narrow sense, but also sinusitis accompanied by inflammation of the paranasal sinus mucous membrane.

[0082] When applied to the nasal mucosa and / or paranasal sinus mucosa, the topical agent of the present invention can improve or prevent various symptoms associated with rhinitis, such as nasal congestion, rhinorrhea, sneezing, itching, etc. In particular, these effects appear more quickly and last longer than those of rhinitis therapeutic agents containing tailed BNP.

[0083] The effect of the topical agent of the present invention against rhinitis generally appears within 8 minutes, preferably within 5 minutes, and more preferably within 3 minutes after application. Moreover, the effect of the topical agent of the present invention on rhinitis as described above generally lasts for 4 hours or more, preferably 8 hours or more, and more preferably 24 hours or more after the onset of the effect.

[0084] When the topical preparation of the present invention is used as a rhinitis treatment agent and / or rhinitis prevention agent, the applicable rhinitis includes, but is not limited to, infectious rhinitis including acute rhinitis and chronic rhinitis; hypersensitive non-infectious rhinitis including combined (flower hypersensitivity) rhinitis, rhinorrhea rhinitis, congestive rhinitis, edema rhinitis and dry rhinitis; irritant rhinitis including physical rhinitis, chemical rhinitis and radiation rhinitis; atrophic rhinitis and idiopathic granulomatous rhinitis; sinusitis such as acute sinusitis, chronic sinusitis (sinusitis), eosinophilic sinusitis, and sinus fungal infection, and the like, and the topical preparation can be used for the purpose of treating or preventing one or more of the above.

[0085] In addition, complex rhinitis includes, for example, allergic rhinitis, including perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis, including vasomotor (essential) rhinitis and eosinophilic rhinitis. Rhinorrhea-type rhinitis includes, for example, gustatory rhinitis, cold air inhalation rhinitis, and senile rhinitis.

[0086] Congestive type rhinitis includes, for example, rhinitis medicamentosa, psychogenic rhinitis, rhinitis of pregnancy, endocrine rhinitis and cold rhinitis. An example of edematous rhinitis is aspirin-induced hypersensitivity rhinitis.

[0087] Among the above, the topical agent of the present invention is particularly effective against hypersensitive non-infectious rhinitis, irritant rhinitis, and sinusitis, preferably against hypersensitive non-infectious rhinitis and chronic sinusitis, more preferably against combined (flower hypersensitivity) rhinitis, rhinorrhea type rhinitis, congestive type rhinitis, edema type rhinitis and dry type rhinitis, and chronic sinusitis.Therefore, the topical agent of the present invention can be used for the purpose of treating or preventing at least one or more types of rhinitis selected from the above group.

[0088] In addition, from the viewpoint of symptoms, since the external preparation of the present invention has the effects as described above, it can be used for any of sneezing-rhinorrhea type rhinitis, nasal congestion type rhinitis, and congestive type rhinitis. Furthermore, the topical preparation of the present invention is effective in improving symptoms even in cases of rhinitis that are difficult to treat with conventional rhinitis treatments such as steroid drugs.

[0089] (6) Other topical preparations In addition, the topical agent of the present invention can be used for other purposes than those mentioned above, with the aim of achieving the effect of the above-mentioned cyclic peptide.In this case, the topical agent of the present invention may be mainly intended to achieve an effect other than the effect of the above-mentioned cyclic peptide.In this case, the cyclic peptide of the present invention, its derivative and / or pharma-ceutically acceptable salt are used to supplement the main effect of the topical agent or to add an effect other than the main effect.

[0090] Such uses include, but are not limited to, body powder, deodorant, depilatory agent, soap, body shampoo, bath additive, hand soap, perfume, sunscreen, anti-inflammatory analgesic, antifungal agent, and the like.

[0091] 2.2 Dosage form By locally administering the topical agent of the present invention to the desired area (e.g., an affected area) of the skin or mucosa, the effects of the active ingredient, a cyclic peptide, its derivative and / or a pharma- ceutical acceptable salt, can be more reliably and rapidly expressed in the vicinity of the application site. Such topical preparations are not particularly limited, but can be, for example, skin preparations, eye drops, ear drops, nasal drops, oral preparations, or suppositories.Among these, when the topical preparation of the present invention is a dermatitis treatment agent, dermatitis prevention agent, antipruritic agent, skin care product, alopecia treatment agent, alopecia prevention agent, hair growth agent, or hair growth agent, it is preferable that it is a skin preparation.On the other hand, when the topical preparation of the present invention is a rhinitis treatment agent and / or rhinitis prevention agent, it is preferable that it is a nasal drop.Furthermore, when it is a corneal disease treatment and / or prevention agent, it is preferable that it is an eye drop.

[0092] When the topical preparation of the present invention is a dermatological preparation, it is not particularly limited, and can be, for example, a solid topical preparation, a liquid topical preparation, a spray, an ointment, a milky lotion, a cream, a gel, or a patch.

[0093] A solid preparation for external use is a solid preparation to be applied or sprayed onto the skin, etc. Examples of such a solid preparation for external use include powdered external powders. A liquid for external use is a liquid preparation for application to the skin, etc. Examples of such liquid for external use include lotions and liniments.

[0094] A spray is a preparation in which an active ingredient is sprayed onto the skin in the form of a mist, powder, foam, paste, etc. Examples of such sprays include aerosols for external use and pump sprays. An ointment is a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base, to be applied to the skin. The ointment may also be a lip balm for topical application to the lips, etc. Creams are semi-solid, oil-in-water or water-in-oil emulsified preparations that are applied to the skin.

[0095] Gels are preparations in the form of a gel that are applied to the skin. Examples of gels include aqueous gels and oily gels. A patch is a preparation that is applied to the skin. Examples of patches include tapes and poultices. Nasal drops are preparations that are administered to the nasal cavity or nasal mucosa. Examples of nasal drops include nasal powders and nasal liquids. Of these, nasal liquids are preferred.

[0096] In any of the above-mentioned dosage forms, the topical preparation of the present invention contains at least the above-mentioned cyclic peptide of the present invention and / or its derivative and / or a pharma- ceutically acceptable salt thereof.

[0097] When the dosage form is a liquid, ointment, cream or gel for external use, the external preparation of the present invention contains the cyclic peptide and / or its derivative and / or a pharma- ceutically acceptable salt thereof at a concentration of, for example, 0.0001 to 1,000,000 μg / g, preferably 0.001 to 10,000 μg / g, more preferably 0.01 to 1,000 μg / g, and even more preferably 0.1 to 100 μg / g. In another embodiment, the concentration may be 1 to 800 μg / g or 3 to 500 μg / g. When the dosage form is a spray, the topical agent of the present invention contains the cyclic peptide and / or its derivative and / or their pharma- ceutically acceptable salt in the concentrate of the spray at a concentration of, for example, 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, 0.01 to 1,000 μg / mL, more preferably 0.1 to 100 μg / mL, and even more preferably 1 to 100 μg / mL. In another embodiment, the concentration may be 1 to 800 μg / mL or 3 to 500 μg / mL.

[0098] When the dosage form is a patch, the topical preparation of the present invention contains the cyclic peptide and / or its derivative and / or a pharma- ceutically acceptable salt thereof at a concentration of, for example, 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may contain the cyclic peptide and / or its derivative and / or a pharma- ceutically acceptable salt thereof at a concentration of, for example, 0.0001 to 1,000 μg / mL, preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may contain the cyclic peptide and / or its derivative at a concentration of, for example, 1 to 800 μg / mL, or 3 to 500 μg / mL. When the dosage form is a nasal drop, particularly a liquid nasal drop, the topical preparation of the present invention contains the cyclic peptide and / or its derivative and / or a pharma- ceutically acceptable salt thereof in the liquid (nasal drop) of the nasal drop, for example, at a concentration of 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may contain the cyclic peptide and / or its derivative and / or a pharma- ceutically acceptable salt thereof in the liquid (nasal drop) of the nasal drop at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0099] The topical agent of the present invention, regardless of the dosage form as described above, can be formulated using methods and constituent materials known to those skilled in the art. Usable constituent materials are not particularly limited, but examples thereof include gelling agents, oily components, higher alcohols, fatty acids, UV absorbers, UV scattering agents, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active components, solvents, antioxidants, fragrances, preservatives, etc.

[0100] As the gelling agent, various gelling agents of organic or inorganic compounds can be used. Examples of the inorganic gelling agent include hydrous or hydrous silicates, such as aluminum silicate (eg, bentonite), magnesium aluminum silicate, and colloidal silica. As the organic compound gelling agent, natural, semi-synthetic or synthetic polymers can be used. Examples of natural and semi-synthetic polymers include polysaccharides such as cellulose, starch, tragacanth, gum arabic, xanthan gum, agar, gelatin, alginic acid and its salts (e.g., sodium alginate and its derivatives), lower alkyl celluloses (e.g., methyl cellulose or ethyl cellulose), carboxy- or hydroxy-lower alkyl celluloses (e.g., carboxymethyl cellulose or hydroxypropyl cellulose), etc. Examples of synthetic polymers include carboxyvinyl polymers, sodium polyacrylate, (vinyl methyl ether / ethyl maleate) copolymers, polymethacrylates, polyvinyl alcohols, polyvinylpyrrolidone, polyacrylic acid or polymethacrylic acid, etc. In addition, as the gelling agent, commercially available gelling agents such as Lubragel NP, Lubragel CG, Lubragel DV, Lubragel MS, Lubragel OIL, Lubragel TW, Lubragel DS, etc. (Ashland) can also be used.

[0101] As the oil, for example, various oil phase components such as esters, ethers, hydrocarbons, silicones and fluorines, as well as animal and vegetable oils and their hardened oils, and naturally occurring waxes can be used. Examples of ester-based oil phase components include glyceryl tri-2-ethylhexanoate, cetyl 2-ethylhexanoate, isopropyl myristate, butyl myristate, isopropyl palmitate, ethyl stearate, octyl palmitate, isocetyl isostearate, butyl stearate, butyl myristate, ethyl linoleate, isopropyl linoleate, ethyl oleate, isocetyl myristate, isostearyl myristate, isostearyl palmitate, octyldodecyl myristate, isocetyl isostearate, and diethyl sebacate. , diisopropyl adipate, isoarachyl neopentanoate, tri(caprylic / capric)glyceryl, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, hexyl laurate, decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isostearyl laurate, isotridecyl myristate, isocetyl myristate, myristate, Isostearyl lysate, isocetyl palmitate, isostearyl palmitate, octyl stearate, isocetyl stearate, isodecyl oleate, octyldodecyl oleate, octyldodecyl linoleate, isopropyl isostearate, cetostearyl 2-ethylhexanoate, stearyl 2-ethylhexanoate, hexyl isostearate, ethylene glycol dioctanoate, ethylene glycol dioleate, propylene glycol dicaprate, propylene glycol dicaprylate, propylene glycol dicaprylate oleate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate, glyceryl tricaprylate, glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearyl isostearate, octyldecyl isostearate, polyglycerin oleate, polyglycerin isostearate,Dipropyl carbonate, dialkyl carbonate (C12-18), triisocetyl citrate, triisoalkyl citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, trioctyl citrate, diisostearyl malate, 2-ethylhexyl hydroxystearate, di-2-ethylhexyl succinate, diisobutyl adipate, diisopropyl sebacate, dioctyl sebacate, cholesteryl stearate, , cholesteryl isostearate, cholesteryl hydroxystearate, cholesteryl oleate, dihydrocholesteryl oleate, phytosteryl isostearate, phytosteryl oleate, isocetyl 12-stearoylhydroxystearate, stearyl 12-stearoylhydroxystearate, and isostearyl 12-stearoylhydroxystearate.

[0102] Examples of hydrocarbon oil phase components include squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, solid paraffin, polybutene, microcrystalline wax, and petrolatum.

[0103] Examples of silicone-based oil phase components include dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethylsiloxane-methylcetyloxysiloxane copolymer, dimethylsiloxane-methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic silicone, trimethylsiloxysilicate, silicone RTV rubber, and the like. Examples of fluorine-based oil phase components include perfluoropolyethers, fluorine-modified organopolysiloxanes, fluorinated pitch, fluorocarbons, fluoroalcohols, and fluoroalkyl-polyoxyalkylene-co-modified organopolysiloxanes.

[0104] Examples of animal and vegetable oils and their hydrogenated oils, and naturally derived waxes include beef tallow, hydrogenated beef tallow, lard, hydrogenated lard, horse oil, hydrogenated horse oil, mink oil, orange roughy oil, fish oil, hydrogenated fish oil, egg yolk, jojoba oil, and other animal and vegetable oils and their hydrogenated oils, avocado oil, almond oil, olive oil, cacao butter, apricot kernel oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, soybean oil, evening primrose oil, camellia oil, corn oil, rapeseed oil, and hydrogenated rapeseed oil. , palm kernel oil, hydrogenated palm kernel oil, palm oil, hydrogenated palm oil, peanut oil, hydrogenated peanut oil, castor oil, hydrogenated castor oil, sunflower oil, grape seed oil, jojoba oil, hydrogenated jojoba oil, macadamia nut oil, medicamentoil, cottonseed oil, hydrogenated cottonseed oil, coconut oil, hydrogenated coconut oil, rosehip oil, and other vegetable oils and their hydrogenated oils; beeswax, high acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax, montan wax, and other waxes.

[0105] Examples of higher alcohols include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, and octyldodecanol.

[0106] Examples of fatty acids include caprylic acid, capric acid, undecylenic acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, linoleic acid, linolenic acid, arachic acid, arachidonic acid, behenic acid, erucic acid, and 2-ethylhexanoic acid.

[0107] Examples of ultraviolet absorbers include para-aminobenzoic acid, amyl para-aminobenzoate, dihydroxypropyl ethyl para-aminobenzoate, glyceryl para-aminobenzoate, ethyl para-aminobenzoate, octyl para-aminobenzoate, octyldimethyl para-aminobenzoate, ethylene glycol salicylate, octyl salicylate, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, glyceryl di-paramethoxycinnamate mono-2-ethylhexanoate, isopropyl paramethoxycinnamate, diethanolamine salt of paramethoxyhydrocinnamate, a mixture of diisopropyl and diisopropyl cinnamate, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and its salts, dihydro ... Examples of the benzotriazole include 2-ethylhexyl-2-cyano-3,3-diphenyl acrylate, phenylbenzimidazole sulfate, 3-(4-methylbenzylidene)camphor, isopropyldibenzoylmethane, 2-ethylhexyl 4-(3,4-dimethoxyphenylmethylene)-2,5-dioxo-1-imidazolidinepropionate, and the like, as well as polymer derivatives and silane derivatives thereof, titanium oxide, zinc oxide, and dispersions thereof. The zinc oxide, titanium oxide, etc. may be surface-treated.

[0108] Examples of percutaneous absorption aids include acetic acid, sodium acetate, limonene, menthol, salicylic acid, hyaluronic acid, oleic acid, N,N-diethyl-m-toluamide (N,N-diethyl-3-methylbenzamide), n-butyl stearate, benzyl alcohol, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, diethyl sebacate, N-methylpyrrolidone, N-ethylpyrrolidone, and lauryl alcohol.

[0109] Examples of powders and pigments include dyes such as Red No. 104, Red No. 201, Yellow No. 4, Blue No. 1, Black No. 401, basic dyes, HC colors, disperse dyes, and direct dyes; lake dyes such as Yellow No. 4 AL Lake and Yellow No. 203 BA Lake; nylon powder, silk powder, urethane powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, and polymers such as polyethylene powder; colored pigments such as yellow iron oxide, red iron oxide, black iron oxide, chromium oxide, carbon black, ultramarine blue, and Prussian blue; and oxides. Examples of such pigments include white pigments such as zinc, titanium oxide, and cerium oxide, extender pigments such as talc, mica, sericite, kaolin, and plate-like barium sulfate, pearl pigments such as titanium mica, metal salts such as barium sulfate, calcium carbonate, magnesium carbonate, aluminum silicate, and magnesium silicate, inorganic powders such as silica and alumina, metal soaps such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, and zinc undecylenate, bentonite, smectite, and boron nitride. There are no particular limitations on the shape (spherical, rod-like, needle-like, plate-like, irregular, flaky, spindle-like, etc.) and particle size of these powders.

[0110] These powders and pigments may be previously surface-treated by a conventionally known surface treatment, such as a fluorine compound treatment, a silicone treatment, a silicone resin treatment, a pendant treatment, a silane coupling agent treatment, a titanium coupling agent treatment, an oil treatment, an N-acylated lysine treatment, a polyacrylic acid treatment, a metal soap treatment, an amino acid treatment, a lecithin treatment, an inorganic compound treatment, a plasma treatment, or a mechanochemical treatment.

[0111] As the surfactant, any of anionic surfactants, cationic surfactants, amphoteric surfactants and nonionic surfactants can be appropriately used. Examples of anionic surfactants include fatty acid soaps, α-acylsulfonates, alkylsulfonates, alkylarylsulfonates, alkylnaphthalenesulfonates, alkyl sulfates, POE alkyl ether sulfates, alkylamide sulfates, alkyl phosphates, POE alkyl phosphates, alkylamide phosphates, alkyloylalkyl taurine salts, N-acylamino acid salts, POE alkyl ether carboxylates, alkylsulfosuccinates, sodium alkylsulfoacetates, acylisethionates, acylated hydrolyzed collagen peptide salts, and perfluoroalkyl phosphates.

[0112] Examples of cationic surfactants include alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, cetostearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, behenyl trimethyl ammonium bromide, benzalkonium chloride, behenic acid amidopropyl dimethyl hydroxypropyl ammonium chloride, stearic acid diethylaminoethyl amide, stearic acid dimethylaminopropyl amide, lanolin derivative quaternary ammonium salts, etc. Also included are tertiary amines such as fatty acid amido dialkyl amines and their salts.

[0113] Examples of the amphoteric surfactant include various amphoteric surfactants of the carboxybetaine type, amidobetaine type, sulfobetaine type, hydroxysulfobetaine type, amidosulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, and amidoamine type. Examples of nonionic surfactants include propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, POE sorbitan fatty acid esters, POE sorbit fatty acid esters, POE glycerin fatty acid esters, POE alkyl ethers, POE fatty acid esters, POE hydrogenated castor oil, POE castor oil, POE·POP copolymers, POE·POP alkyl ethers, polyether-modified silicone alkanolamide laurate, alkylamine oxides, hydrogenated soybean phospholipids, hydroxylated soybean phospholipids, polymeric surfactants, and biosurfactants. Natural surfactants can also be used, and examples of such surfactants include lecithin, saponin, and sugar-based surfactants.

[0114] Examples of polyhydric alcohols and sugars include ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3-butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan, etc. Chemically modified versions of these can also be used.

[0115] Examples of the polymer include acrylic acid ester / methacrylic acid ester copolymers, vinyl acetate / crotonic acid copolymers, vinyl acetate / crotonic acid / vinyl neodecanoate copolymers, methyl vinyl ether maleic acid half esters, t-butyl acrylate / ethyl acrylate / methacrylic acid copolymers, vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymers, vinyl acetate / crotonic acid copolymers (Rubyset CA: manufactured by BASF), vinyl acetate / crotonic acid / vinyl pyrrolidone copolymers, vinyl pyrrolidone / acrylate copolymers, acrylate / acrylamide copolymers, vinyl acetate / butyl maleate / isobornyl acrylate copolymers, carboxyvinyl polymers, acrylic Examples of such polymers include anionic polymers such as acrylic acid / alkyl methacrylate copolymers, amphoteric polymers such as acetic acid amphoteric products of dialkylaminoethyl methacrylate polymers, and amphoteric polymers such as acrylic acid octylacrylamide / hydroxypropyl acrylate / butylaminoethyl methacrylate copolymers, cationic polymers such as quaternary products of vinylpyrrolidone / dimethylaminoethyl methacrylate and methylvinylimidazolium chloride / vinylpyrrolidone copolymers, and nonionic polymers such as polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate copolymers, and vinylcaprolactam / vinylpyrrolidone / dimethylaminoethyl methacrylate copolymers. Additionally, naturally occurring polymeric compounds such as cellulose or derivatives thereof, keratin and collagen or derivatives thereof, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharides, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, gum arabic, crystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, curdlan, gellan gum, and dextran, as well as glucooligosaccharides, fucose-containing polysaccharides, and rhamnose-containing polysaccharides can also be suitably blended.

[0116] Examples of bioactive ingredients include substances that impart some kind of bioactivity to the skin when applied to the skin. For example, they are ingredients that have effects such as whitening, anti-inflammation, anti-aging, UV protection, slimming, tightening, antioxidant, hair growth and hair growth, hair inhibition, moisturizing, promoting blood circulation, antibacterial and germicidal, cold and warm sensation, promoting wound healing, irritation relief, pain relief, and cell activation, and examples of such ingredients include plant extracts, seaweed extracts, vitamins and their derivatives, amino acids, various peptides other than cyclic peptides, sodium hyaluronate, mucopolysaccharides and other biopolymers, ceramides, phytosphingosine, cholesterol, phytosterols and other intercellular lipid components or similar components, enzyme components, etc.

[0117] Examples of suitable ingredients include angelica extract, avocado extract, amacha extract, althea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, isoflavones, ginkgo extract, fennel extract, turmeric extract, oolong tea extract, angelica tree extract, echinacea leaf extract, scutellaria extract, phellodendron bark extract, coptis jasmine extract, barley extract, Hypericum perforatum extract, white lamb's foot extract, watercress extract, orange extract, cacao extract, seawater dried products, seaweed extract, hydrolyzed elastin, hydrolyzed wheat Powder, hydrolyzed silk, pumpkin seed extract, chamomile extract, carrot extract, mugwort extract, licorice extract, kalkade extract, kakyoku extract, kiwi extract, cinchona extract, cucumber extract, guanosine, gardenia extract, kumazasa extract, sophora flavescens extract, cranberry extract, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, gentiana extract, black tea extract, yeast extract, burdock extract, rice bran fermented extract, rice germ oil, comfrey extract, collagen, cowberry extract, saishin extract , psychedelic extract, umbilical cord extract, salvia extract, soapwort extract, bamboo extract, hawthorn extract, Japanese pepper extract, shiitake mushroom extract, rehmannia extract, lithospermum extract, perilla extract, linden extract, meadowsweet extract, peony extract, calamus root extract, birch extract, horsetail extract, ivy extract, hawthorn extract, elderberry extract, yarrow extract, peppermint extract, sage extract, mallow extract, cnidium rhizome extract, swertia japonica extract, soybean extract, soybean extract, soybean extract, Fermentation extract, thyme extract, tea extract, clove extract, Imperata cylindrica extract, tangerine extract, evening primrose extract, centella extract, terminalia extract, angelica extract, calendula extract, peach kernel extract, spruce extract, dokudami extract, tomato extract, natto extract, carrot extract, garlic extract, wild rose extract, hibiscus extract, burdock extract, parsley extract, honey, banana flower extract, witch hazel extract, parietaria extract, yarrow extract, bisabolol, loquat extract, coltsfoot extract, butterbur bud extract, bupleurum extract,Examples of such extracts include butcher's broom extract, grape extract, propolis, loofah extract, safflower extract, peppermint extract, linden extract, peony extract, hop extract, pine extract, horse chestnut extract, skunk cabbage extract, soapberry extract, melissa extract, peach extract, cornflower extract, eucalyptus extract, saxifrage extract, yuzu extract, coix seed extract, mugwort extract, lavender extract, apple extract, lychee (litchi) extract, lettuce extract, lemon extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, and royal jelly extract.

[0118] In addition, moisturizing ingredients such as biopolymers such as deoxyribonucleic acid, mucopolysaccharides, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, and hydrolyzed eggshell membrane, polypeptides such as amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidone carboxylate, betaine, whey, trimethylglycine, and lysine-arginine condensates, intercellular lipid components such as sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, phytosterol derivatives, and phospholipids, or similar components thereof, are also included. Anti-inflammatory agents such as ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, hydrocortisone, and tea tree oil, vitamins such as vitamin A and its derivatives, vitamin B2 and its derivatives, vitamin B6 and its derivatives, vitamin C and its derivatives, vitamin D and its derivatives, vitamin E and its derivatives, calcium pantothenate, biotin, and nicotinamide, active ingredients such as allantoin, diisopropylamine dichloroacetate, and 4-aminomethylcyclohexanecarboxylic acid, tocopherol, calorie Antioxidants such as tinoids, flavonoids, tannins, lignans, saponins, etc.; cell activators such as α-hydroxy acids and β-hydroxy acids; blood circulation promoters such as γ-oryzanol and vitamin E derivatives; wound healing agents such as retinol and retinol derivatives; skin whitening agents such as arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, and glutathione; cepharanthine, licorice extract, capsicum tincture, hinokitiol, iodized garlic extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, nicotinic acid, Cotinic acid derivatives, calcium pantothenate, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropyl methylphenol, estradiol, ethinyl estradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, tacanal, camphor, salicylic acid, vanillyl nonyl amide, vanillyl nonanoate, piroctone olamine, glyceryl pentadecanoate, L-menthol, mononitroguaiacol, resorcinol, gamma-aminobutyric acid, benzethonium chloride, mexiletine hydrochloride,Examples of hair growth agents include auxin, female hormones, cantharis tincture, cyclosporine, zinc pyrithione, hydrocortisone, minoxidil, polyoxyethylene sorbitan monostearate, peppermint oil, and Sasanishiki extract.

[0119] Examples of the antioxidant include sodium hydrogen sulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolylbiguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxytoluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoids, flavonoids, tannins, lignans, saponin, and plant extracts having antioxidant effects such as apple extract and clove extract.

[0120] Examples of the solvent include physiological saline, purified water, ethanol, lower alcohols, ethers, LPG, fluorocarbons, N-methylpyrrolidone, fluoroalcohols, volatile linear silicones, and next-generation fluorocarbons.

[0121] In addition, since the cyclic peptide and / or its derivative and / or their pharma- ceutically acceptable salts of the present invention can be used for the manufacture of topical preparations as described above, the present invention also relates to the use of the cyclic peptide and / or its derivative and / or their pharma- ceutically acceptable salts of the present invention for the manufacture of topical preparations.

[0122] 3. How to use topical medications Next, a method for using the topical agent of the present invention will be described. A method for using the topical agent of the present invention comprises applying the above-mentioned topical agent of the present invention to the skin and / or mucosa of a subject.

[0123] In addition to humans, the subject may include, but is not limited to, vertebrates such as birds and mammals. In particular, mammals include, for example, rodents such as mice, rats, gerbils, hamsters, and guinea pigs, laboratory animals such as rabbits, livestock such as pigs, cows, goats, horses, sheep, and minks, pets such as dogs and cats, and primates such as humans, monkeys, cynomolgus monkeys, rhesus monkeys, marmosets, orangutans, and chimpanzees. On the other hand, humans may be excluded from the subject.

[0124] Furthermore, the skin and / or mucosa of the subject to which the topical agent is applied may be the skin or mucosa of any part of the subject, and may be applied to, for example, the skin or mucosa of the head (scalp), face, neck, arms, torso, hands, feet, etc. A more specific method for using the topical agent of the present invention is as follows.

[0125] (1) Methods for treating and preventing dermatitis When the topical preparation of the present invention is used as a dermatitis treatment or prevention agent, the topical preparation can be directly applied to the target skin and / or mucous membrane site (for example, an affected area with dermatitis). The frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Note that, since the effect of the topical preparation of the present invention lasts for a long time, it exerts a sufficient effect even when applied relatively infrequently, for example, once a day. In addition, the dosage is not particularly limited, but for example, the total amount of the cyclic peptide of the present invention and its derivatives and their pharma- ceutically acceptable salts per application can be 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may be contained at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0126] (2) Methods for reducing or eliminating itching When the topical preparation of the present invention is used as an antipruritic agent, the topical preparation can be applied directly to the target skin and / or mucous membrane site. The frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. In addition, the dosage is not particularly limited, but for example, the total amount of the cyclic peptide of the present invention and its derivatives and their pharma- ceutically acceptable salts per application can be 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may be contained at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0127] (3) How to use cosmetics When the topical preparation of the present invention is used as a cosmetic, the topical preparation can be applied directly to the desired skin and / or mucous membrane site. The frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. In addition, the dosage is not particularly limited, but for example, the total amount of the cyclic peptide of the present invention and its derivatives and their pharma- ceutically acceptable salts per application can be 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may be contained at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0128] (4) Methods for treating and preventing alopecia, and methods for growing and regrowing hair When the topical preparation of the present invention is used as an agent for treating alopecia, an agent for preventing alopecia, a hair growth agent or a hair restorer, the topical preparation can be directly applied to the target area (for example, the scalp or a hair loss area of ​​the skin). The frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. In addition, the dosage is not particularly limited, but for example, the total amount of the cyclic peptide of the present invention and its derivatives and their pharma- ceutically acceptable salts per application can be 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may be contained at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0129] (5) Methods for treating and preventing rhinitis When the topical preparation of the present invention is used as a rhinitis treating agent or a rhinitis preventive agent, the topical preparation can be directly applied to the target site (for example, the nasal mucosa). The frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. In addition, the dose is not particularly limited, but for example, the total amount of the cyclic peptide of the present invention and its derivatives and their pharma- ceutically acceptable salts per application to each nasal cavity can be 0.0001 to 1,000,000 μg / mL, preferably 0.001 to 10,000 μg / mL, more preferably 0.01 to 1,000 μg / mL, even more preferably 0.1 to 100 μg / mL, and particularly preferably 1 to 100 μg / mL. In another embodiment, it may be contained at a concentration of 1 to 800 μg / mL or 3 to 500 μg / mL.

[0130] 4. Pharmaceuticals Next, the pharmaceutical agent of the present invention will be described. The pharmaceutical agent of the present invention comprises one or more of the cyclic peptides of the present invention or their derivatives, or pharma- ceutically acceptable salts thereof.

[0131] As described above, the cyclic peptide or its derivative or a pharma- ceutical acceptable salt thereof of the present invention, like BNP, is considered to bind to a receptor NPR-A (also known as GC-A) having a guanylate cyclase domain, promote the production of cyclic guanosine monophosphate (cGMP), and have, for example, a diuretic effect, a vasodilatory effect, renin / aldosterone secretion inhibition, sympathetic nerve inhibition, hypertrophy inhibition, etc. Furthermore, these compounds of the present invention are considered to have superior efficacy and potency, particularly superior immediate action, compared to BNP.

[0132] Therefore, the medicine of the present invention can be used for the same purposes as conventional medicines containing BNP as an active ingredient. Diseases to which the pharmaceutical of the present invention can be applied include, but are not limited to, the various diseases described above, as well as hypertension, unstable angina, acute myocardial infarction, edematous diseases, renal failure, heart failure, immune diseases, obesity, metabolic syndrome, and the like.

[0133] Furthermore, the dosage form of the medicament of the present invention is not particularly limited, and in addition to the above-mentioned external preparations, examples thereof include preparations for oral administration such as tablets, capsules, granules, powders, oral liquid preparations, syrups, oral jellies, etc.; preparations for oral application such as oral tablets, oral sprays, oral semisolid preparations, and mouthwashes; preparations for injection such as injections and infusions; preparations for dialysis such as dialysis agents, inhalants, eye drops, eye ointments, ear drops, vaginal tablets, vaginal suppositories, etc. EXAMPLES

[0134] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to these examples.

[0135] 1. Preparation of Cyclic Peptides First, a cyclic peptide consisting of the amino acid sequence represented by formula Ia was synthesized. Specifically, a peptide synthesizer was used to sequentially bond amino acids to form a linear peptide consisting of 17 amino acids by solid-phase peptide synthesis. After that, the protecting groups at Cys1 and Cys17 were removed, and iodine (I2) treatment was performed to oxidatively form cysteine ​​bonds between the amino acid residues, forming a cyclic peptide. The obtained composition containing the cyclic peptide was purified by reversed-phase high performance liquid chromatography (reverse-phase HPLC) and then freeze-dried to obtain a purified cyclic peptide as a white powder.

[0136] In addition, mass spectrometry of the obtained cyclic peptide was performed. The HPLC conditions are as follows. Equipment: Agilent 1100 Flow rate: 1.0ml / min Eluent A: 0.1% trifluoroacetic acid / water Eluent B: 0.1% trifluoroacetic acid / acetonitrile Gradient: 80% eluent B isocratic The conditions for mass spectrometry (MS) are as follows: Equipment: Thermo Finnigan LCQ Advantage Ionization method: electrospray ionization Analysis method: Ion trap method

[0137] As a result, m / z=901.83 ([M+2H]2+) and m / z=1801.84 ([M+H]+) were observed, and the above peptide was determined to be the desired cyclic peptide with the formula (C 72 H 120 N 24 O 24 S3), the molecular weight (1802.07) and mass number (1800.8069) were confirmed to be consistent with the theoretical values ​​calculated from the above-mentioned compound.

[0138] Furthermore, the purity of the above peptide was measured by HPLC under the following conditions. Column: Discovery C18, 4.6mm x 250mm, particle size 5 microns Column temperature: room temperature Eluent A: 0.1% trifluoroacetic acid / water Eluent B: 0.1% trifluoroacetic acid / acetonitrile Gradient: 10-30% eluent B / 20 min Flow rate: 1.2ml / min Temperature: room temperature Injection volume: 20μl Detector: UV detector (detection wavelength 215 nm) As a result of the measurement, the purity of the obtained protein was confirmed to be 99.2%.

[0139] 2. Preparation of the drug product 2.1 Preparation of gel formulations A gel-based formulation containing a cyclic peptide consisting of an amino acid sequence represented by formula Ia (in the following examples, "B-ring" refers to such a cyclic peptide represented by formula Ia) (B-ring gel formulation, Example) and a gel-based formulation containing human BNP (BNP gel formulation, Comparative Example) were prepared as follows. 0.1 g of methyl paraoxybenzoate (product name: Mekkins M, manufactured by Ueno Pharmaceuticals), 0.2 g of phenoxyethanol, and 3.0 g of 1,2-pentanediol were weighed into a single container, heated to 60 to 70° C. to form a homogeneous solution, and then charged into a mixing kettle. Next, 6.0 g of concentrated glycerin was added to the mixing kettle, followed by a mixture of 0.44 g of carboxyvinyl polymer (trade name: Carbopol 940, manufactured by Lubrizol Advanced Materials) and 0.08 g of xanthan gum (trade name: Keltrol T, manufactured by CP Kelco), which was then stirred with a paddle to thoroughly disperse them.

[0140] Next, 83.95 g of purified water was gradually added while stirring with a paddle, and the kettle temperature was heated to 70-80°C while stirring with a paddle and a disperser to dissolve the dispersed contents to obtain a solution. After that, the disperser was stopped, and cooling was started immediately after confirming that the contents in the solution had dissolved. When the kettle temperature reached approximately 40°C, 6.0 g of Lubragel NP (2.7 g of glycerin, 0.06 g of carboxyvinyl polymer, 0.018 g of sodium polyacrylate, 3.222 g of water) manufactured by Ashland was added to the solution and mixed uniformly with a paddle. Then, 0.230 g of potassium hydroxide was added to neutralize the solution, and when the kettle temperature reached 25°C, the rotation of the paddle was stopped to produce a gel base.

[0141] Next, 20.1 mg of a cyclic peptide (B ring) consisting of an amino acid sequence represented by formula Ia was dissolved in 144 mL of physiological saline to obtain 0.131 mL of the B ring solution, which was uniformly mixed with 10 g of the gel base obtained above by stirring to produce a gel base preparation (B ring gel preparation) with a B ring concentration of about 1 μM (about 1.8 μg / g). In the same manner, gel base preparations with B ring concentrations of about 0.3 μM (about 0.54 μg / g), about 0.5 μM (about 0.9 μg / g), and about 2.0 μM (about 3.6 μg / g) were produced. In the following examples, unless otherwise specified, the "B ring gel preparation" used had a B ring concentration of about 1 μM. Next, 0.2 mL of the BNP solution obtained by dissolving 20.5 mg of human BNP-32 (American Peptide Company) in 118 mL of physiological saline was mixed uniformly with 10 g of the gel base obtained above to produce a gel base preparation (BNP gel preparation) with a BNP-32 concentration of about 1 μM. In the same manner, gel base preparations with BNP-32 concentrations of about 0.5 μM and 2.0 μM were produced. In the following examples, unless otherwise specified, the "BNP gel preparation" used had a BNP concentration of about 1 μM.

[0142] 2.2 Preparation of nasal drops A nasal drop containing a cyclic peptide (B-ring) consisting of an amino acid sequence represented by formula Ia (B-ring nasal drop, Example) and a nasal drop containing human BNP (BNP nasal drop, Comparative Example) were prepared as follows.

[0143] First, a cyclic peptide (B ring) consisting of an amino acid sequence represented by formula Ia was dissolved in saline, and the concentration was adjusted to obtain a B ring nasal solution with a B ring concentration of approximately 1 μmol / l (approximately 1.8 μg / g). Next, the Ring B nasal solution was filled into a metered dose nasal spray container (manufactured by AS ONE Corporation), and the amount sprayed per time was adjusted to 100 μl (0.1 ml) to obtain Ring B nasal solution.

[0144] Similarly, a BNP nasal solution with a BNP concentration of 1 μmol / l was obtained from human BNP (American Peptide Company), which was then filled into a metered-dose nasal spray container (As One Corporation). The amount sprayed per dose was then adjusted to 100 μl (0.1 ml), yielding a BNP nasal solution.

[0145] 3. Confirmation of dermatitis treatment effect 3.1 Confirmation of efficacy of B-ring gel formulation For subjects suffering from various dermatitis, the above-mentioned B-ring gel preparation was applied to the affected area, and changes in symptoms were observed before and after application. If possible, for the same subjects as a comparison, the above-mentioned BNP gel preparation was applied to the affected area to which the B-ring gel preparation was not applied, and changes in symptoms were observed before and after application. Itching sensation was evaluated on a 10-point scale for each affected area using a VAS (visual analogue scale). The test results are shown in Tables 1 to 7 together with the subjects' ages, sexes, symptoms, and prescriptions for the subjects.

[0146] [Table 1]

[0147] [Table 2]

[0148] [Table 3]

[0149] [Table 4]

[0150] [Table 5]

[0151] [Table 6]

[0152] [Table 7]

[0153] [Table 8]

[0154] As shown in Tables 1 to 8, in all subjects and in all types of dermatitis, relief or disappearance of various dermatitis symptoms was observed at the sites where the Ring B gel preparation was applied. In particular, when the B-ring gel formulation was applied, itching sensation was observed to improve and disappear immediately after application. In dermatitis, patients generally have a tendency to scratch the area where they feel itchy when they feel itchy, which can be one of the causes of dermatitis becoming severe. However, by significantly improving and disappearing the itching sensation, it is possible to prevent dermatitis from becoming severe. In addition, the effect of the B-ring gel preparation was superior to that of the BNP gel preparation in all cases. In particular, the B-ring gel preparation had a more immediate and sustained effect and a stronger antipruritic effect than the BNP gel preparation. It was confirmed that these effects could not be obtained with a gel base.

[0155] 3.2 Comparison of B-ring gel preparations and gel base using the left-right painting method The B-ring gel formulation and gel base were applied to the affected areas of subjects suffering from various types of dermatitis, and changes in symptoms before and after application were observed (table below). [Table 9]

[0156] 4. Confirmation of effectiveness as a cosmetic The effects of cosmetics containing B rings were confirmed by evaluating the results when they were used as gels, bath additives, hair cosmetics (shampoo, rinse) or body soaps containing B rings. 4.1.1 Confirmation of skin quality improvement effect (comparison between B-ring gel preparation and BNP gel preparation) The subjects were prescribed the above-mentioned B-ring gel preparation and BNP gel preparation. The B-ring gel preparation was applied to the right side of the cheeks and around the eyes of each subject, and the BNP gel preparation was applied to the left side, and the changes in skin condition were observed and compared (see the table below). The changes in skin condition were judged based on the subject's subjective evaluation and the objective observation by the present inventor as a doctor. [Table 10]

[0157] In addition, the following are examples of applying the B-ring gel formulation without applying it to the left and right sides separately (see table below). Changes in skin condition were measured using the same method as above.

[0158] [Table 11]

[0159] As described above, it has been shown that the B ring of the present invention has a moisturizing effect on the skin and can smooth the skin texture. Furthermore, it is effective in improving skin quality such as whitening (age spots, dullness) and anti-aging (sagging, firmness, large wrinkles), as well as improving the condition of mucous membranes such as chapped lips.

[0160] In all subjects, the areas where the B-ring gel preparation was applied showed a significant improvement in skin quality and its maintenance compared to the areas where the B-ring gel preparation was applied. Specifically, the following effects were significantly observed in the areas where the B-ring gel preparation was applied: skin was smoothed, skin was moisturized, skin texture was improved, skin became firm and taut, skin became soft, dryness was suppressed, fine lines were less noticeable, moisture and oil in the skin was replenished and maintained, wrinkles around the eyes were shallower and less noticeable, stinging sensation in the skin was eliminated, itching was relieved and suppressed, dryness of the skin was alleviated, and healthy skin was maintained.

[0161] Furthermore, particularly in subjects in their 20s and 30s, there were effects such as the improvement and disappearance of wrinkles, improvement in sagging cheeks, and the replenishment and maintenance of moisture, water, and oil in the skin, with the skin becoming firmer and more taut, the cheeks lifting, and also the elimination of stinging sensation in the skin and the alleviation of dryness. These effects were more pronounced in the areas where the B-ring gel preparation was applied than in the areas where the BNP gel preparation was applied, and the effects were even greater than in the areas where the BNP gel was applied. Furthermore, particularly in subjects in their 40s and 50s, after application of the B-ring gel preparation, there was a rapid improvement in sagging, wrinkles, and dryness, and the skin became firmer and dullness and blemishes became less noticeable; these effects were greater than those seen when BNP gel was applied.

[0162] The onset of effect was significantly faster with the B-ring gel formulation than with the BNP gel formulation. Specifically, in most cases, wrinkles began to disappear and become less noticeable about 2 minutes after application of the B-ring gel formulation, and the skin became plumper and firmer. Furthermore, this effect continued for at least several hours afterwards. There was no irritation associated with application of the B-ring gel formulation.

[0163] Figure 1 shows a photograph of the right side of the face of a subject in his 60s after application of the B-ring gel formulation. In the same subject, 20 minutes after application of the B-ring gel formulation, the effect of moisturizing the skin, giving it luster and softness, tightening the skin, smoothing the texture, giving it firmness, and making large wrinkles less noticeable was observed. Compared with the BNP gel formulation as a control, the results show that the cyclic peptide of the present invention is effective not only for fine lines, but also for wrinkles and sagging, and also has the effect of making spots and dullness less noticeable.

[0164] 4.1.2 Confirmation of skin quality improvement effect (comparison between B-ring gel formulation and gel base) In order to investigate whether the gel base contributes to the effects of the B-ring gel preparation and the BNP gel preparation, the B-ring gel preparation was applied to the right side of the face of three subjects, and the gel base was applied to the left side of the face, and changes in the condition of the subjects' facial skin were observed (table below).

[0165] [Table 12]

[0166] As a result, all subjects felt a tingling sensation in the areas where the gel base was applied, and the dryness of the skin did not improve. In addition, no effects such as smoothing of the skin texture or tightening of pores were observed in the areas where the gel base was applied. On the other hand, in all subjects, the skin in the areas where the B-ring gel formulation was applied became moist, soft, and moisturized.

[0167] 4.2 Observation of the condition of the mucosa after application of the B-ring gel preparation The B-ring gel formulation was applied to normal subjects with chapped lips, and the changes in the condition of the lip mucosa were observed (see the table below). The changes in the condition of the mucosa were judged based on the subjective evaluation of the subjects and the objective observation by the present inventor as a physician.

[0168] [Table 13]

[0169] As described above, it has been confirmed that the cyclic peptide of the present invention has the effect of improving the condition of the mucous membrane, and furthermore, has an immediate effect in this regard.

[0170] 4.3 Observation of the condition of the scalp and hair after application of the B-ring gel formulation The B-ring gel formulation was applied to normal subjects with scalp and hair symptoms, and the changes in the condition of the scalp and hair were observed (see table below). The changes in the condition of the scalp and hair were judged based on the subjective evaluation of the subjects and the objective observation by the inventor as a physician. [Table 14]

[0171] As described above, the BNP cyclic peptide of the present invention can moisturize and maintain the scalp and hair, as well as replenish and maintain appropriate moisture and oil, improve and prevent dryness, and cleanse the scalp and hair. Furthermore, it is effective in suppressing scalp itching and dandruff, and is also effective in preventing thinning hair and hair loss, promoting hair growth, hair growth, and hair growth, and is also effective in improving hair loss after illness or childbirth, hair care, etc.

[0172] 4.4 Observation of skin condition when bath additives containing B ring are used The subjects were bathed once a day for 14 days in 37-41°C hot water (100ml of 20μM solution of B-ring dissolved in 200L of hot water) containing 0.01μM B-ring, and the skin condition of the subjects was compared with that of subjects bathed in plain water (hot water only) (Table 14). The changes in skin condition were judged based on the subject's subjective evaluation and the objective observation by the present inventor as a doctor.

[0173] [Table 15]

[0174] As described above, the bath additive containing the B ring of the present invention not only relieves heat rash, cracked and chapped skin, and eczema, but also has an improving effect on eczema. Furthermore, it has been shown to be effective in improving skin conditions, as it improves dryness and skin pain and itching.

[0175] 4.5 Observation of scalp and hair condition or skin condition when using hair cosmetics (shampoo, rinse) or body soap containing B ring

[0176] 4.5.1 A shampoo containing B ring was formulated and manufactured with the following composition: [Table 16] After A and B were dissolved by heating at 70℃, B was added to A and stirred and mixed. C was further added at 40-35℃ while stirring, and the mixture was cooled to room temperature while still stirring.

[0177] 4.5.2 A treatment containing B ring was formulated and manufactured with the following composition. [Table 17] After dissolving A and B at 80℃, while keeping A and B at 80℃, A was stirred with a homomixer and B was gradually added to A to emulsify. C was then added and the mixture was cooled to 35℃ while still stirring.

[0178] 4.5.3 A body soap containing B ring was formulated and manufactured with the following composition. [Table 18] After A and B were dissolved by heating at 80℃, B was gradually added to A while stirring. Furthermore, C was added at 40-35℃ while stirring, and the mixture was cooled to room temperature while stirring.

[0179] The shampoo, rinse or body wash manufactured as described above was used once a day for 14 days, and the results on the scalp and hair condition or skin condition of the subjects were evaluated (see table below). Changes in skin condition, such as scalp dandruff and erythema, were evaluated visually by the subjects, while scalp itchiness, moist feeling, combing ability, luster, and firmness were evaluated by the subjects' subjective evaluation. [Table 19] As described above, the use of the hair product containing the B ring of the present invention has an immediate effect of improving itching, erythema, and dryness of the scalp.Also, it has been shown that the use of the hair product containing the B ring of the present invention is effective in improving symptoms of thinning hair and hair loss when used continuously for more than two weeks.Furthermore, it has been shown that the use of the body soap containing the B ring of the present invention has an effect of improving dry skin and sensitive skin.

[0180] 5. Confirmation of effectiveness of alopecia treatment The B-ring gel preparation and the BNP gel preparation were applied, and the effects on various symptoms related to hair loss were observed (see the table below). The changes in symptoms were judged based on the subjective evaluation of the subjects and the objective observation by the present inventor as a doctor.

[0181] [Table 20]

[0182] [Table 21]

[0183] [Table 22]

[0184] 5.2 Case summary In the case of the subjects with the above-mentioned female pattern alopecia, androgenic alopecia, alopecia universalis, alopecia serpentina, and alopecia multiplex, when the B-ring gel preparation according to the embodiment is applied, hair loss is significantly reduced, the area of ​​terminal hair growth is expanded, and the growth is also faster than when the BNP gel preparation is used as a control (see FIG. 2). Furthermore, the existing hair is made firm and its stiffness is strengthened. In both cases, the improvement of the symptoms is more significant than when the BNP gel preparation according to the comparative example is applied. That is, the B-ring gel preparation has a better efficacy against the above-mentioned symptoms than the BNP gel preparation. Furthermore, the B-ring gel formulation improved seborrheic dermatitis, cleansed the scalp, and suppressed dandruff. It also prevented gray hair, promoted black hair growth, and improved thinning hair. Furthermore, it was found that the itching suppression effect was high, suppressing itching within 10 minutes. In some cases, itching was suppressed within 3 minutes after application.

[0185] 6. Confirmation of the effectiveness of treatment for rhinitis 6.1 Cases The subjects were sprayed with Ring B nasal drops and BNP gel nasal drops, and the effects on rhinitis, etc. were observed (Table 17). Changes in symptoms were evaluated based on subjective evaluation by the subjects and objective observation by the present inventor as a physician.

[0186] [Table 23]

[0187] [Table 24]

[0188] [Table 25]

[0189] [Table 26]

[0190] 6.2 Case Summary In all the above cases, when the B-ring nasal spray according to the embodiment is applied, both rhinorrhea and nasal congestion are improved and resolved more quickly than when the BNP nasal spray according to the comparative example is applied. That is, the B-ring nasal spray is more immediate than the BNP nasal spray. In addition, the efficacy of the B-ring nasal spray is equal to or greater than the efficacy of the BNP nasal spray, and the duration of its efficacy is long, and it can suppress the recurrence of symptoms.

[0191] In addition, the time points at which nasal congestion and rhinorrhea symptoms improved for the above-mentioned cases are summarized in the table below to the extent that they could be understood from the case information. [Table 27]

[0192] 7. Analysis of the binding state of human BNP to type A receptor As described above, the B-ring compound of the present invention has superior pharmacological effects against various diseases, etc., compared to conventional BNP. This pharmacological effect is supported by the results of the three-dimensional structure analysis of the compound conducted by the inventors, and the following experimental report is provided for reference. To investigate the binding state between human BNP (BNP-32) and its receptor, type A receptor (NPR-A), we performed in silico analysis using homology modeling based on the three-dimensional structure. Swiss-Pdb viewer and SWISS-MODEL were used for modeling.

[0193] 7.1 Template Structure First, prior to the above analysis, a template structure was selected for examining the binding state between human BNP and the type A receptor. The three-dimensional structure of the complex between rat NPR-A and rat ANP peptide (PDB ID: 1T34) was used as the template structure. Rat NPR-A is a homodimer consisting of chains A and B. The three-dimensional structure of such rat NPR-A has been determined by X-ray crystal structure analysis in a state in which 21 residues from Cys7 to Arg27 of rat ANP are bound. The three-dimensional structure of rat NPR-A was obtained from the Protein Data Bank, a database of protein three-dimensional structures. The amino acid identity between human NPR-A and rat NPR-A is 85%.

[0194] 7.2 BNP peptide model In this study, the peptide model for BNP used was the amino acid sequence of the Cys10 to Arg30 region of human BNP (BNP-32, SEQ ID NO: 13, Ser-Pro-Lys-Met-Val-Gln-Gly-Ser-Gly-Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-Ile-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys-Lys-Val-Leu-Arg-Arg-His) shown below (SEQ ID NO: 14, Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-Ile-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys-Lys-Val-Leu-Arg). In the above peptide model, the amino acid sequence of the B ring of the present invention corresponds to Cys10 to Cys26 in the above human BNP, i.e., the region Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-Ile-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys (sequence number 15).

[0195] 7.3 Homology Modeling To infer the amino acid residues involved in the binding of human NPR-A to human BNP, a complex model of the BNP peptide bound to human NPR-A was constructed by homology modeling. Specifically, a human BNP peptide model was modeled based on the template structure of rat ANP peptide, and a model structure of human NPR-A was modeled based on the template structure of rat NPR-A. Next, from the amino acid residues detected between the human BNP peptide model and human NPR-A, residues directly involved in the interaction were predicted.

[0196] As a result, it was shown that the BNP peptide model is bound to the human NPR-A dimer in a state sandwiched between its A chain and B chain. The amino acids in the amino acid sequence used in the model (SEQ ID NO: 14, Cys-Phe-Gly-Arg-Lys-Met-Asp-Arg-Ile-Ser-Ser-Ser-Ser-Gly-Leu-Gly-Cys-Lys-Val-Leu-Arg) are expressed as amino acids (numbers). That is, the numbers in parentheses represent the numbers counted from the N-terminus of the above amino acid sequence, and for example, Phe2 refers to the amino acid that is the second Phe counted from the N-terminus of the above peptide model.

[0197] In the constructed complex model, hydrophobic bonds by the side chain of Phe2, hydrogen bonds by the main chain of Phe2, and hydrogen bonds by the side chains of Arg4, Met6, Arg8, Ser10, and Ser11 were predicted between the BNP peptide model and the A chain of NPR-A. Note that Phe2, Arg4, Met6, Arg8, Ser10, and Ser11 in the BNP peptide model correspond to Phe11, Arg13, Met15, Arg17, Ser19, and Ser20, respectively, in human BNP. In other words, this result suggested that these amino acid residues in human BNP may be residues that contribute to the activation of NPR-A.

[0198] 7.4 Discussion From the above, the in silico structural analysis of human BNP suggests that the amino acid residues in the cyclic portion of the BNP contribute to the activation of NPR-A, whereas the amino acid residues in the tail do not. It was also suggested that the BNP cyclic structure is a smaller molecule than BNP-32 and can bind more easily and quickly. When a peptide with a BNP cyclic structure was actually applied clinically, it was confirmed that the therapeutic effect of the BNP cyclic structure was obtained more quickly than that of BNP-32. This clinical result is consistent with the in silico analysis that the BNP cyclic structure contributes to the activation of NPR-A and can bind more easily and quickly than BNP-32. Therefore, the BNP cyclic structure is considered to be a different substance with a superior therapeutic effect to the general BNP peptide.

[0199] On the other hand, NMR analysis has revealed that ANP does not take a specific three-dimensional structure in an aqueous solution, and it is believed that BNP does the same. In other words, if the amino acid residues in the cyclic portion of human BNP contribute to binding with human NPR-A, it was speculated that the amino acid residues in the tail, due to their large fluctuations, make it difficult for human BNP to enter the narrow BNP binding site between the A and B chains of human NPR-A. Therefore, unlike conventionally known human BNP, the cyclic portion of human BNP is a relatively low molecular weight, and it was thought that it could enter the BNP binding site of NPR-A more easily and quickly. It was also speculated that the cyclic portion of human BNP has a higher affinity for human NPR-A than BNP-32. This supported the clinical results described in this specification that a peptide containing only the cyclic portion of BNP can obtain a therapeutic effect more quickly than BNP-32.

[0200] In addition, in order to predict the effect of the cyclic structure (B ring) of BNP derived from species other than humans on the human type A receptor, a complex model of human NPR-A and BNP ring derived from pig, bird, and rat was created, and the interaction was predicted. As a result, it was suggested that the effect of the present invention can be fully expected even if BNP rings of animals other than humans, such as pig, bird, and rat, are used, as long as they show affinity to human NPR-A.

[0201] 8. Prediction of replaceable amino acid residues in the BNP cyclic moiety Using the constructed model structure of the complex, the possibility of substituting amino acid residues other than those predicted to interact was examined. Specifically, to examine whether the substituted peptide can bind to NPR-A when amino acid residues other than those predicted to interact with the BNP were replaced with other amino acids, a mutant model of BNP was created and the interaction was analyzed. Modeling was performed using the Swiss-Pdb viewer.

[0202] Specifically, among the amino acid residues of human BNP, Gly12, Lys14, Asp16, Ile18, Ser21, Ser22, Gly23, Leu24, and Gly25 were targeted and their possibility of substitution with other amino acids was examined from the following viewpoints. · No steric hindrance occurs when binding to NPR-A. No clashes between atoms are observed in the model structures of NPR-A and BNP mutants. -Does not affect the electrostatic potential of the surface. -The value of intramolecular energy does not increase significantly (there is no unnatural angle or twist in the bonds between atoms). -NPR-A does not form hydrogen bonds between the chains of BNP and BNP that are not normally found within the chains of BNP. -No cavities or gaps are formed.

[0203] The intramolecular energy values ​​were calculated using the Compute Energy command in the Swiss-Pdb viewer. The intramolecular energy was calculated in kilojoules / mol (Kj / mol) from the total of the bond length, bond angle, torsion, bond energy, etc. between atoms.

[0204] As a result of the analysis, it was shown that the amino acid residues that could be replaced were Gly12, Lys14, Ile18, Ser21, Ser22, Leu24 and Gly25 in the amino acid residues of human BNP (see the table below). [Table 28]

[0205] From the above, it was suggested that even when the cyclic portion of human BNP, i.e., the peptide represented by formula Ia, undergoes substitutions of amino acid residues corresponding to the substitutions described in the above table, the peptide having such substitutions exerts the same effect as the peptide consisting of the amino acid sequence represented by formula Ia.

[0206] 9. Confirmation of therapeutic effects of cyclic peptides with amino acid substitutions Next, the cyclic peptide with some amino acids substituted was subjected to the following test to confirm its effect. The method for producing the cyclic peptide and the method for confirming the amino acid sequence of the produced peptide were the same as the method for producing the cyclic peptide and the mass spectrometry method described above.

[0207] 9.1 Confirmation of effects on scalp or hair The obtained cyclic peptide was mixed with purified water at 3, 15, 30, 100, and 500 μg / ml and applied to the affected area. Note that formulations A to E in the table refer to cyclic peptide concentrations of 3, 15, 30, 100, and 500 μg / ml, respectively. When treated with purified water, there was no effect, confirming that this was not a placebo effect.

[0208] [Table 29-1]

[0209]

Table 29-2

[0210]

Table 29-3

[0211]

Table 29-4

[0212]

Table 29-5

[0213]

Table 29-6

[0214]

Table 29-7

[0215]

Table 29-8

[0216]

Table 29-9

[0217]

Table 29-10

[0218]

Table 29-11

[0219] [Table 29-12]

[0220] [Table 29-13]

[0221] The above results demonstrate that even a cyclic peptide in which some of the amino acids of the cyclic peptide of the present invention have been substituted exhibits the same effects as the cyclic peptide represented by formula Ia.

[0222] In particular, when applied to a site such as a hair loss site or a hair growth site, it has the effect of preventing hair loss at the application site, promoting hair growth or hair growth, giving hair firmness and strength, increasing volume, and dramatically reducing hair loss. In addition, at the application site, it has the effect of hair nourishment, hair growth promotion, and improving and preventing thinning hair. In this case, the hair that grows tends to be hard and not gray. In addition, compared with other active ingredients used in conventional alopecia treatment agents, such as BNP, for example, even in cases of intractable multiple alopecia and serpentine alopecia, hair growth can be confirmed the next day after only one application, and the obtained effect is significantly sustained, such as hair growth continuing even after application is stopped. In AGA and healthy people, the immediate effect of giving hair firmness and strength the next day, increasing volume, and dramatically reducing hair loss is observed, and the effect continues even after application is stopped. In addition, it has the effect of improving and preventing dermatitis. Therefore, it can improve or prevent skin inflammation associated with alopecia. Such an effect is advantageous when alopecia is aggravated due to the condition of the skin at the application site such as the scalp. Furthermore, when the topical agent of the present invention is applied to the skin as described above, it exerts moisturizing effect and texture shaping effect at the application site. It can remove dandruff and itching and suppress their occurrence, and also moisturize hair and scalp, improve and prevent dryness, and keep scalp and hair healthy. It can also improve seborrheic state. On the other hand, when used as an alopecia treatment agent or alopecia prevention agent, the applicable alopecia is not particularly limited, but for example, the following alopecias can be mentioned, and it can be used for the purpose of treating or preventing one or more of them.

[0223] (Acquired alopecia) (i) Alopecia without scarring or skin lesions (alopecia areata, androgenetic alopecia, seborrheic alopecia, pityriasis grisea, female pattern alopecia, pregnancy-related alopecia, malignant alopecia, senile alopecia, alopecia totalis, alopecia multiplex, serpiginosa, drug-induced alopecia, cancer chemotherapy drug-induced alopecia and alopecia due to radiation exposure, traumatic or mechanical alopecia, alopecia associated with nutritional or metabolic disorders, alopecia associated with endocrine abnormalities, telogen effluvium (postpartum alopecia, post-hyperthermia)) (ii) Alopecia due to skin lesions or diseased skin (alopecia due to infection, alopecia due to tumor, alopecia due to inflammation) (iii) Cicatricial alopecia (hair loss due to skin infections or inflammatory cell infiltration) (Congenital alopecia) Diffuse alopecia, congenital atrichosis, alopecia in hereditary syndromes, focal alopecia, nevus, aplasia cutis, congenital triangular alopecia

[0224] In particular, it is effective against acquired alopecia, preferably against alopecia without scar or skin lesion, more preferably against alopecia areata, androgenetic alopecia, seborrheic alopecia, pityriasis grisea, female pattern alopecia, pregnancy alopecia, malignant alopecia, senile alopecia, alopecia totalis, alopecia multiplex, serpentine alopecia, drug-induced alopecia, cancer chemotherapy drug-induced alopecia and radiation exposure-induced alopecia, traumatic / mechanical alopecia, alopecia associated with nutritional disorder / metabolic disorder, alopecia associated with endocrine abnormality, and telogen effluvium.Therefore, the topical preparation of the present invention can be used for the purpose of treating or preventing at least one or more types of alopecia selected from the above-mentioned group. A single application of 3μg / ml to 500μg / ml to the affected area mentioned above showed immediate improvement and elimination of itching, dandruff, redness of the scalp, inflammation, etc., and just one application showed hair growth, hair regrowth, hair firmness, increased volume, and dramatic reduction in hair loss, with the effect continuing for more than a week. Furthermore, continued application for about a week further improved these effects, and even after stopping application, hair growth and hair thickening continued for one to two weeks, with almost no hair loss.

[0225] 9.2 Checking the effect on the skin The obtained cyclic peptide was mixed with purified water at 3, 15, 30, 100, and 500 μg / ml and applied to the affected area. Note that formulations A to E in the table refer to cyclic peptide concentrations of 3, 15, 30, 100, and 500 μg / ml, respectively. Note that when the peptide was not mixed and treatment was performed with purified water, there was no effect, so it was confirmed that this was not a placebo effect.

[0226]

Table 30-1

[0227]

Table 30-2

[0228]

Table 30-3

[0229]

Table 30-4

[0230]

Table 30-5

[0231]

Table 30-6

[0232]

Table 30-7

[0233]

Table 30-8

[0234]

Table 30-9

[0235]

Table 30-10

[0236] [Table 30-11]

[0237] [Table 30-12]

[0238] From the above results, it was demonstrated that the cyclic peptide of the present invention in which some amino acids are substituted has the same effect as the cyclic peptide represented by formula Ia.In addition, even when the substituted cyclic peptides are mixed and applied, the same effect can be obtained by applying an effective amount of the cyclic peptide.

[0239] In particular, subjects with atopic dermatitis, eczema, etc., showed immediate effects such as disappearance of itching immediately after applying 3μg / ml to 500μg / ml to the affected area, epithelialization of erythema, infiltration, papules, and scratches, cessation of exudation, and epithelialization of cracks. In addition, the effect was sustained for more than one week with just one application. When applied to healthy or rough skin, it exerts a moisturizing effect within a few minutes of application, improving dryness, imparting and maintaining appropriate elasticity and flexibility to the skin and mucous membranes, softening the skin, and making the skin and mucous membranes firm and firm. It also improves fine lines and sagging at the application site, and makes dullness and blemishes less noticeable. These effects were observed to last for more than a week with a single application.

[0240] 9.3 Confirmation of the effect on the nose The obtained cyclic peptide was mixed with saline at 3, 15, 30, 100, and 500 μg / ml, and approximately 0.1 ml was instilled into the nasal cavity. Note that formulations A to E in the table refer to cyclic peptide concentrations of 3, 15, 30, 100, and 500 μg / ml, respectively. Note that when the peptide was not mixed and the treatment was with saline, there was no effect, so it was confirmed that this was not a placebo effect.

[0241] [Table 31-1]

[0242] [Table 31-2]

[0243] [Table 31-3]

[0244] [Table 31-4]

[0245] [Table 31-5]

[0246] [Table 31-6]

[0247] The above results demonstrate that even a cyclic peptide in which some of the amino acids of the cyclic peptide of the present invention have been substituted exhibits the same effects as the cyclic peptide represented by formula Ia.

[0248] In particular, when applied to the nasal mucosa and / or paranasal sinus mucosa, it can improve or prevent various symptoms associated with rhinitis, such as nasal congestion, rhinorrhea, sneezing, and itching. In addition, the rhinitis is not particularly limited, and examples thereof include infectious rhinitis including acute rhinitis and chronic rhinitis; hypersensitive non-infectious rhinitis including combined (flower hypersensitivity) rhinitis, rhinorrhea rhinitis, congestion rhinitis, edema rhinitis, and dry rhinitis; irritant rhinitis including physical rhinitis, chemical rhinitis, and radiation rhinitis; atrophic rhinitis and idiopathic granulomatous rhinitis; acute sinusitis, chronic sinusitis (sinusitis), eosinophilic sinusitis, and sinus fungal disease, and the like, and can be used for the purpose of treating or preventing one or more of the above. Examples of complex rhinitis include allergic rhinitis, including perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis, including vasomotor (essential) rhinitis and eosinophilic rhinitis. Examples of rhinorrhea-type rhinitis include gustatory rhinitis, cold air inhalation rhinitis, and senile rhinitis. Congestive type rhinitis includes, for example, rhinitis medicamentosa, psychogenic rhinitis, rhinitis of pregnancy, endocrine rhinitis and cold rhinitis. An example of edematous rhinitis is aspirin-induced hypersensitivity rhinitis.

[0249] Among the above, it is particularly effective against hypersensitive non-infectious rhinitis, irritant rhinitis, and sinusitis, preferably against hypersensitive non-infectious rhinitis and chronic sinusitis, and more preferably against combined (flower hypersensitivity) rhinitis, rhinorrhea type rhinitis, congestive type rhinitis, edema type rhinitis and dry type rhinitis, and chronic sinusitis.Therefore, the external preparation of the present invention can be used for the purpose of treating or preventing at least one or more types of rhinitis selected from the above group. In addition, from the viewpoint of symptoms, since it has the above-mentioned effects, it can be used for any of sneezing-rhinorrhea type rhinitis, nasal congestion type rhinitis, and congestive type rhinitis. After 0.1ml of 3μg / ml~500μg / ml was applied to each nostril and affected area, it immediately stopped nasal discharge, improved nasal congestion, and stopped itching of the nasal mucosa and sneezing, and the effect lasted for a day with just one application of nasal drops, and in some cases, the effect lasted for more than a week.In addition, since there was no local irritation at all, it can be used safely even by subjects who do not want to use nasal drops due to the strong local irritation caused by conventional steroid drugs that have been used to treat rhinitis.

[0250] Taking the above examples into consideration, examples of amino acids that can be substituted in the cyclic peptide of the present invention are summarized below, but the present invention is not limited to these.

[0251] [Table 32]

Claims

1. Formula I: 【Chemistry 1】 During the ceremony, X １ represents Gly, Val, Ala, Ser or Thr, X ２ represents Arg, Gln or His, X ３ represents Lys or Arg, X ４ represents Met, Leu or Ile, X ５ indicates Ile or Val, X ６ represents Ser or Gly, X ７ represents Ser or Ala, X ８ represents Ser, Gln, Val, Ala, Thr, Leu, Ile or Met, X ９ represents Ser, Val, Ala or Thr, X １０ represents Gly or Arg, X １１ represents Leu, Met, Ile, Val or Ala, X １２ represents Gly, Ser or Ala, The line connecting the two Cys represents a disulfide bond. The amino acid sequence represented by The amino acid sequence does not have any peptide bonds other than those between the amino acids constituting the amino acid sequence. A cyclic peptide or a derivative thereof, or a pharma- ceutically acceptable salt thereof.

2. X １ ~X １２ However, the following (1) to (12): (1) X １ represents Gly, Val, Ala, Ser or Thr; (2) X ２ represents Arg, Gln or His; (3) X ３ represents Lys or Arg; (4) X ４ represents Met, Leu or Ile; (5) X ５ represents Ile or Val; (6) X ６ represents Ser or Gly; (7) X ７ represents Ser or Ala; (8) X ８ represents Ser, Gln, Val, Ala, Thr, Leu, Ile or Met; (9) X ９ represents Ser, Val, Ala or Thr; (10) X １０ represents Gly or Arg; (11) X １１ represents Leu, Met, Ile, Val or Ala, and (12) X １２ represents Gly, Ser or Ala; One or more selected from the group consisting of 2. The cyclic peptide according to claim 1, or a derivative thereof, or a pharma- ceutically acceptable salt thereof.

3. The cyclic peptide according to claim 1, which is selected from the cyclic peptides of SEQ ID NOs: 3 to 8 and 16 to 75, or a derivative thereof, or a pharma- ceutically acceptable salt thereof.

4. The derivatives react with hydrogen atoms, hydroxyl groups, carboxyl groups, amino groups, and imino groups in the cyclic peptide. The cyclic peptide or its derivative or a pharma- ceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the cyclic peptide or its derivative is substituted with a substituent that can be substituted.

5. A cyclic peptide or a derivative thereof, or a pharma- ceutically acceptable salt thereof, which is formed by deleting one to four amino acids in a cyclic peptide represented by any one of SEQ ID NOs: 3 to 7, or by substituting or adding other amino acids, and has a function equivalent to that of the cyclic peptide represented by each of the above formulas.

6. An external preparation comprising one or more of the cyclic peptide and / or its derivative according to any one of claims 1 to 5 and / or a pharma- ceutical acceptable salt thereof.

7. 7. The external preparation according to claim 6, which is a dermatitis treatment agent, a dermatitis prevention agent, an antipruritic agent, an anti-inflammatory agent, an agent for promoting wound epithelialization, or a material for skin care products.

8. The external preparation according to claim 7, wherein the skin care product is for moisturizing, and / or for preventing and improving rough skin, and / or for sebum care and acne care, and / or for easing irritation and anti-inflammation, and / or for whitening, and / or for preventing aging, and / or for preventing and easing UV damage, and / or for slimming, and / or for cleansing the skin.

9. The external preparation according to claim 6, which is a bath additive, a body cleanser or a hair cleanser.

10. The external preparation according to claim 6, which is an agent for treating alopecia, an agent for preventing alopecia, a hair growth agent and / or a hair regrowth agent.

11. The external preparation according to claim 6, which is a rhinitis treatment agent and / or a rhinitis preventive agent.

12. The external preparation according to claim 6, which is a cosmetic preparation.

13. The external preparation according to any one of claims 6 to 12, which is in the form of a solid, semisolid, powder, liquid, spray, ointment, cream, emulsion, gel, or patch.

14. The external preparation according to any one of claims 6 to 13, which is used as a medicine, a quasi-drug, or a cosmetic.

15. 5. Use of the cyclic peptide according to any one of claims 1 to 4 and / or its derivative and / or a pharma- ceutical acceptable salt thereof for the manufacture of an external preparation.

16. The external preparation according to any one of claims 6 to 14, for application to the skin and / or mucous membranes.

17. The external preparation according to claim 16, wherein the mucous membrane is the lips, oral cavity, nasal cavity, eye or vagina.

18. The external preparation according to claim 16, which is a method for treating and / or preventing dermatitis, a method for reducing or eliminating itching, a method for treating sores or ulcers caused by eczema or the like, or a skin care method.

19. The external preparation according to claim 16, which is a method for treating and / or preventing alopecia and / or a method for promoting hair growth and / or a method for cultivating hair.

20. The external preparation according to claim 16, which is a method for treating and / or preventing rhinitis.

21. A medicine comprising at least one of the cyclic peptides or derivatives thereof according to any one of claims 1 to 5, or pharma- ceutically acceptable salts thereof.

22. The pharmaceutical agent according to claim 21, which is a therapeutic agent for hypertension, unstable angina, acute myocardial infarction, edematous disease, renal failure, heart failure, immune disease, obesity, or metabolic syndrome.

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