CNP cyclic peptide and pharmaceuticals, topical preparations and cosmetics containing the cyclic peptide

Abstract

The present invention aims to provide novel peptides that exhibit rapid onset of efficacy and efficacy and a long period of remission maintenance, as well as pharmaceuticals and topical preparations containing these peptides, particularly preventive or therapeutic agents for dermatitis, rough skin, rhinitis, alopecia, and thinning hair, and hair growth agents, hair tonics, antipruritics, and skincare products. [Solution] The present invention achieves the above objective by providing a cyclic peptide or its derivative or a pharmaceutically acceptable salt thereof, having an amino acid sequence represented by formula I, wherein the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the amino acid sequence.

Description

[Technical Field]

[0001] This invention relates to CNP cyclic peptides and pharmaceuticals, topical preparations, and cosmetics containing said cyclic peptides. [Background technology]

[0002] CNP (C-type natriuretic peptide), a member of the human NP family, is known to be produced specifically in the brain and not in the heart, unlike ANP and BNP, which belong to the same family. Although its natriuretic utilization and blood pressure-lowering effects are weaker than those of ANP and BNP, it is known to have a strong effect in increasing intracellular cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells and other cells (Non-Patent Literature 1). It is thought that its physiological role is one other than maintaining homeostasis of body fluid volume and blood pressure.

[0003] CNPs are known to be highly conserved in terms of their constituent amino acids across different species, with virtually no differences between them, and their structure is characterized by a common cyclic and tail portion. In this regard, it has been shown that the minimum active structure for increasing cGMP in vascular smooth muscle cells is the cyclic portion of CNP (hereinafter sometimes simply referred to as the C ring), and various CNP mutants and derivatives have been reported (Patent Documents 1 and 6). Recently, several therapeutic drugs and treatment methods utilizing CNP have become known (Patent Documents 1-5), and some reports suggest that CNP cyclic peptides are effective against arthritis (Patent Document 6).

[0004] However, while the use of steroids and tacrolimus remains the mainstream treatment for dermatitis, their use is discouraged for infants and some individuals due to strong side effects such as skin atrophy with long-term topical application, an increased risk of adrenal insufficiency in cases with widespread skin lesions, and an increased risk of infection due to immunosuppressive effects. Ultimately, however, the reality is that these drugs must be used to control the condition, despite the strong side effects. In this regard, dermatitis treatments containing CNP have been reported to have no such side effects and to be able to suppress symptoms effectively (Patent Documents 2-4). Similarly, while steroids are widely used for rhinitis, their therapeutic effect is often short-lived compared to the side effects, and there are cases where the expected effect is not achieved. In contrast, rhinitis treatments containing CNP have been reported to have a longer duration of effect and no side effects (Patent Documents 2-4). Furthermore, while various drugs are used for alopecia, none have been able to produce the desired effects. However, alopecia treatments containing CNP have been demonstrated to have significant hair growth and hair restoration effects (Patent Documents 2-4). [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] Patent No. 2809533 [Patent Document 2] International Publication No. 2010 / 062459 [Patent Document 3] International Publication No. 2011 / 064644 [Patent Document 4] International Publication No. 2011 / 024973 [Patent Document 5] U.S. Patent No. 7,276,481 [Patent Document 6] U.S. Patent Application Publication No. 2007 / 0197434 [Non-patent literature]

[0006] [Non-Patent Document 1] Furuya M, Takehisa M, Minamitake Y, Kitajima Y, Hayashi Y, Ohnuma N, Ishihara T, Minamino N, Kangawa K, Matsuo H Biochem Biophys Res Commun. 1990 Jul 16;170(1):201-8. [Overview of the Initiative] [Problems that the invention aims to solve]

[0007] As mentioned above, CNP and CNP cyclic peptides are considered useful substances for treating various diseases such as arthritis. However, in order to obtain higher therapeutic and treatment effects than before, there is a need to develop substances with even stronger pharmacological effects and efficacy, as well as substances with superior rapid onset and sustained effects. Furthermore, there is a demand for formulations that are less expensive than those currently available.

[0008] Incidentally, further enhancing the efficacy, duration of effect, and immediate onset of action of drugs is extremely significant from the perspective of reducing the number and frequency of necessary treatments, alleviating the suffering of patients and users, improving quality of life, and enhancing daily mental, physical, and social satisfaction (QOL). For example, in dermatitis, symptoms such as itching, erythema, and flushing may be present in the affected area, or in diseases like psoriasis, where erythema accompanied by thick scales is seen throughout the body, the QOL is often significantly impaired not only by the cosmetic problems but also by the shedding of scales. If these symptoms can be quickly alleviated, the patient's suffering will be reduced. Also, rhinitis is often accompanied by nasal congestion and runny nose symptoms, and if these symptoms can be quickly suppressed, it will lead to a reduction in the frequency of nasal congestion, thus reducing the patient's discomfort. Furthermore, when using hair loss treatments, alopecia treatments, hair tonics, and hair regrowth agents, if the treatment, hair regrowth, hair growth, and hair loss suppression effects are quickly achieved, it is possible to improve the user's QOL.

[0009] Focusing on these points, the inventors attempted to explore novel materials and new applications by referring to the structure of CNP. Therefore, an object of the present invention is to provide a novel substance, a novel peptide having stronger medicinal effects and efficacy compared to the prior art, a medicament and an external preparation containing the same, particularly a preventive or therapeutic agent for dermatitis, rhinitis, alopecia, a hair growth agent, a hair tonic, an antipruritic agent, a cosmetic, a skin care product, etc.

Means for Solving the Problems

[0010] Conventionally, it has been known that cyclic CNP is the minimum active structure of cGMP in smooth muscle cells, but the physical property values of the cyclic CNP are not clear. In addition, there are therapeutic agents obtained by adding various modifications to CNP. However, the present inventor has deliberately focused on only the ring portion of CNP, which is not necessarily considered to have a high activity value, and has conducted intensive research on the cyclic peptide obtained by deleting the tail portion. As a result of creating a novel substance based on CNP cyclic, the present inventor has obtained completely new findings such as the high efficacy, medicinal effect, rapid onset of effect, and increased persistence of effect of such cyclic peptides. Furthermore, as a result of continuing the research, the present invention has been completed. That is, the present invention relates to the following.

[0011] [1] Formula I:

Chemical Formula

[0012] [6] A cyclic peptide or derivative thereof, or a pharmaceutically acceptable salt thereof, formed by deleting one to six amino acids in the cyclic peptide described in [4], or by substituting or adding other amino acids, and having a function equivalent to the cyclic peptide represented by each of the above formulas. [7] A topical preparation comprising one or more cyclic peptides and / or derivatives thereof as described in any one of items [1] to [6], and / or pharmaceutically acceptable salts thereof. [8] The topical preparation described in [7], which is a dermatitis treatment agent, dermatitis preventive agent, antipruritic agent, anti-inflammatory agent, epidermal regeneration promoter, or ingredient for skin care products. [9] The topical preparation described in [8], wherein the skincare product is for moisturizing and / or preventing and improving rough skin and / or preventing and improving sensitive skin and / or preventing and improving dry skin and / or improving sebum and acne care and / or soothing irritation and anti-inflammatory and / or whitening and / or anti-aging and / or preventing and improving wrinkles and sagging and / or dullness and dark circles and / or preventing and improving photosensitivity and / or preventing and mitigating UV damage and / or slimming and / or cleansing the skin.

[10] External preparations as described in [8], including bath additives, body washes, hair washes, rinses / treatments, tonics, hair oils, hair lotions, and scalp care products.

[0013]

[11] The topical preparation described in [7] is a treatment for alopecia, a preventive agent for alopecia, a hair growth agent and / or a hair regrowth agent and / or a hair loss preventive agent or anti-hair loss cosmetic.

[12] A topical preparation as described in [7] for preventing and improving dandruff and itching, and / or for improving and preventing dryness of the hair and scalp, and / or for improving and preventing seborrheic dermatitis of the scalp.

[13] The topical preparation described in [7], which is a treatment for rhinitis and / or a preventive agent for rhinitis and / or a treatment for sinusitis and / or a preventive agent for sinusitis.

[14] A cosmetic, as described in [7], for external use.

[15] An external preparation according to any one of the items [7] to

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

[16] A topical preparation according to any one of items [7] to

[15] , comprising a cyclic peptide / and / or derivative thereof, and / or a pharmaceutically acceptable salt thereof, according to any one of items [1] to [5], at a concentration of 0.0001 to 1,000,000 μg / mL.

[17] An external preparation used as a pharmaceutical, quasi-drug, or cosmetic, as described in any one of items [7] to

[16] .

[0014]

[18] Use for the manufacture of topical preparations of cyclic peptides and / or derivatives thereof as described in any one of items [1] to [5], and / or pharmaceutically acceptable salts thereof.

[19] A method of using a topical preparation, comprising applying the topical preparation described in any one of items [7] to

[17] to the target skin and / or mucous membrane.

[0015]

[20] The method of use of the topical preparation described in

[18] , wherein the mucous membrane is the lips, oral cavity, nasal cavity, eye, or vagina. [twenty one] Methods of using the topical preparations described in

[18] , which are methods for treating and / or preventing dermatitis, for reducing or eliminating itching, for treating erosions and ulcers, or for skin care. [twenty two] Methods of use of the topical preparation described in

[18] , which are methods for the treatment and / or prevention of dermatitis selected from the group consisting of eczema, atopic dermatitis, contact dermatitis, photosensitivity, psoriasis, acne, cystic acne, seborrheic dermatitis, and itching. [twenty three] Methods of use for the treatment and prevention of rough skin, sensitive skin, dry skin, oily skin, photosensitivity, wrinkles, sagging, dullness, dandruff and itchiness, as described in

[18] . [twenty four] Methods for using the topical preparation described in

[18] , which are methods for treating and / or preventing thinning hair, alopecia, and / or promoting hair growth and / or nourishing hair, and for preventing and / or preventing hair loss. [twenty five] Methods for using the topical preparations described in

[18] , which are methods for preventing or reducing dandruff and itching, and / or for improving or preventing dryness of the hair and scalp, and / or for preventing or improving seborrheic dermatitis of the scalp.

[26] Methods of use for topical preparations described in

[18] , which are methods for the treatment and / or prevention of rhinitis and sinusitis.

[0016]

[27] A pharmaceutical product comprising one or more cyclic peptides or derivatives thereof described in any one of items [1] to [5], or pharmaceutically acceptable salts thereof.

[28] A drug described in

[27] for the treatment of hypertension, unstable angina, acute myocardial infarction, edematous diseases, renal failure, heart failure, immune diseases, autoimmune diseases, allergic diseases, cancer, digestive system diseases, Crohn's disease, ulcerative colitis, obesity, and metabolic syndrome. [Effects of the Invention]

[0017] The present invention provides novel cyclic peptides and compositions containing them. Such compositions can be applied to topical agents for the prevention or treatment of dermatitis, rhinitis, and alopecia, as well as to hair growth agents, hair tonics, hair loss preventatives, and antipruritics, and can be provided as pharmaceuticals, quasi-drugs, skincare products, cosmetics, etc.

[0018] The topical preparation of the present invention generally exhibits significantly greater efficacy against dermatitis than conventional topical steroid preparations and CNPs. Furthermore, it possesses superior rapid action compared to these preparations and substances, with symptoms generally beginning to improve within 3 minutes. Its effects are also greater, more sustained, and result in a longer remission period.

[0019] Furthermore, when the topical preparation of the present invention is applied to the skin or mucous membrane of a person suffering from dermatitis, it can rapidly alleviate or eliminate various perceptible symptoms and conditions such as itching, pain, heat, tightness, infiltration, and erythema caused or that may occur due to dermatitis, while also improving the objective symptoms of dermatitis.

[0020] Furthermore, the topical preparation of the present invention exhibits a moisturizing effect at the application site, and if a stratum corneum is present at the application site, it exhibits an effect of refining the skin texture at the application site, resulting in a refined skin texture, improvement of dry skin and rough skin, softer and more moisturized skin, shallower and less noticeable wrinkles, prevention of photosensitivity, prevention and improvement of wrinkles and sagging, prevention and improvement of dullness and dark circles, and even improvement of chapped lips.

[0021] Furthermore, when applied to the scalp, the topical preparation of the present invention prevents hair loss at the application site, promotes hair growth or development, prevents hair shedding, and thickens hair. In this case, the hair that grows tends to be coarse and not gray. Moreover, these effects appear earlier and are greater compared to other active ingredients used in conventional alopecia treatments, such as CNP. In addition, the effects of thickening hair, promoting faster hair growth, and improving thinning hair are remarkable in both male pattern baldness and female pattern baldness (M-type and O-type).

[0022] Furthermore, the topical agent of the present invention also has a rapid effect on rhinitis, its effect is significant and sustained, and the remission period is long.

[0023] Furthermore, since the cyclic peptide of the present invention shares a structural component with CNP, a hormone naturally present in the body, it is considered to have few side effects, and no side effects have been discovered or reported to date. Also, because it is mainly administered through the skin, the amount of the CNP ring, which has a large molecular weight (>500D) and is not hydrophobic, absorbed into the body is thought to be very small. In other words, as long as the appropriate dosage is used or when applied topically to the skin, systemic side effects and hemodynamic effects are presumed to be minimal. Therefore, it can be administered long-term to patients who require long-term administration, such as patients with chronic dermatitis. In addition, because the topical preparation of the present invention causes little irritation when applied topically, it can be applied to people with sensitive skin, especially to hypersensitive areas such as the face and neck. It can also be used by pregnant and breastfeeding women.

[0024] Furthermore, the above-mentioned cyclic peptide can also be used as an ingredient in topical preparations such as dermatitis treatment / prevention agents, rhinitis treatment / prevention agents, alopecia treatment / prevention agents, hair growth agents, hair restoration agents, hair loss treatment / prevention agents, and antipruritics. In addition, it can be used as an ingredient in skincare products, quasi-drugs, and cosmetics. Moreover, it is certainly possible to use the above-mentioned cyclic peptide as a substitute for CNP in pharmaceuticals that utilize the activity of CNP, such as pharmaceuticals for the treatment of hypertension, unstable angina, acute myocardial infarction, edematous diseases, renal failure, heart failure, immune diseases, autoimmune diseases, allergic diseases, cancer, digestive system diseases, obesity, and metabolic syndrome. Furthermore, because the above-mentioned cyclic peptide is a smaller peptide than CNP, its manufacturing cost is fixed, and preparations using it can be provided at a lower cost compared to CNP. [Brief explanation of the drawing]

[0025] [Figure 1] This figure shows the results of applying C-ring and CNP gel formulations separately to the lower legs of patients with psoriasis (P6) using a left-right smear method. [Figure 2] This figure shows the results before and after application of a C-ring gel formulation to a patient (A11) with male pattern baldness (M-type and O-type). [Modes for carrying out the invention]

[0026] The present invention will now be described in detail based on preferred embodiments. As stated herein, CNP cyclic peptides (hereinafter sometimes referred to as "CNP cyclic peptides," "C-rings," or "C-ring compounds") are derived from wild-type CNP. However, wild-type CNP includes not only those derived from humans, but also those from species having the same sequence as human wild-type CNP, such as, but not limited to, monkeys, pigs, birds, and rats. Therefore, C-ring peptides also include not only those derived from humans, but also, but not limited to, those derived from monkeys, pigs, birds, and rats, and it goes without saying that these can naturally substitute for the effects of the present invention. Furthermore, the cyclic peptides of the present invention also include those obtained by mutating the cyclic peptides. That is, the variants of the present invention can be obtained by deleting amino acids in the cyclic peptide, substituting with other amino acids, or adding amino acids as long as they have CNP activity.

[0027] 1. Cyclic peptide, its derivative and pharmaceutically acceptable salts thereof First, the cyclic peptide, its derivative and pharmaceutically acceptable salts thereof of the present invention will be described.

[0028] Formula I:

Chemical formula

[0029] In another aspect of the present invention, the present invention is a cyclic peptide having the amino acid sequence of SEQ ID NO: 1 and having CNP activity, and the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the amino acid sequence. In addition, the amino acid sequence of SEQ ID NO: 3 can be removed from the amino acid sequence of SEQ ID NO: 1.

[0030] Such cyclic peptides, like CNPs, bind to the receptor NPR-B (also known as GC-B), which has a guanylate cyclase domain, and promote the production of cGMP. Therefore, it is presumed that they have effects such as diuretic effects, vasodilatory effects, inhibition of renin and aldosterone secretion, inhibition of the sympathetic nerve, and inhibition of hypertrophy.

[0031] Another aspect of the present invention is: Formula I: [ka] (Sequence ID 1) During the ceremony, X 1 This indicates Gly or Ala, X 2 This indicates Leu, Ala, or Met. X 3 This indicates Ile or Val, X 4 This refers to Ser, Thr, Ala, Val, Ile, or Leu. X 5 This indicates Ser, Thr, or Ala. X 6 This represents Leu, Ala, Val, Ile, Met, or Phe. The line connecting the two Cys represents a disulfide bond. It has an amino acid sequence represented by, However, equation II: [ka] In the formula, the line connecting the two Cys represents a disulfide bond. Excluding cyclic peptides (SEQ ID NO: 3) consisting of amino acid sequences represented by, The amino acid sequence does not have peptide bonds other than those between the amino acids that make up the amino acid sequence. A cyclic peptide or its derivative, or a pharmaceutically acceptable salt thereof.

[0032] Furthermore, the above cyclic peptide is defined in formula (I) above, X 1 This indicates Gly, and, X 3 It is preferable that this is a cyclic peptide exhibiting Ile (SEQ ID NO: 2). Furthermore, the cyclic peptide of the present invention has an amino acid sequence represented by formula (I), [ka] (Sequence ID 3) In the formula, the line connecting the two Cys represents a disulfide bond. It is more preferable that the peptide is a cyclic peptide consisting of the amino acid sequence represented by formula (II). The amino acid sequence represented by formula (II) is the cyclic portion of CNP (hereinafter sometimes referred to as CNP-17). That is, the human wild-type CNP (hereinafter sometimes referred to as CNP-22) is Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys (SEQ ID NO: 4), and the peptide in question corresponds to the peptides from the 6th Cys to the 22nd Cys, counting from the N-terminus of the human wild-type CNP.

[0033] In another embodiment of the present invention, the amino acid sequence represented by formula (II) (SEQ ID NO: 3) can be removed from the peptide consisting of the amino acid sequence represented by formula (I) (SEQ ID NO: 1).

[0034] In another embodiment of the present invention, the amino acid sequence may be selected from SEQ ID NOs: 60 to 62, and the amino acid sequence may not have peptide bonds other than those between the amino acids constituting the sequence, and may be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof.

[0035] Furthermore, in another embodiment of the present invention, a cyclic peptide or derivative thereof, or a pharmaceutically acceptable salt thereof, may have an amino acid sequence selected from SEQ ID NOs. 54 to 56, wherein the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the sequence.

[0036] Furthermore, in another embodiment of the present invention, a cyclic peptide or derivative thereof, or a pharmaceutically acceptable salt thereof, may have an amino acid sequence selected from SEQ ID NOs. 42 to 47, wherein the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the sequence.

[0037] Furthermore, in another embodiment of the present invention, a cyclic peptide or its derivative or a pharmaceutically acceptable salt thereof may have an amino acid sequence selected from SEQ ID NOs. 22 to 31, wherein the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the sequence.

[0038] In another embodiment of the present invention, a cyclic peptide or its derivative or a pharmaceutically acceptable salt thereof may have an amino acid sequence selected from SEQ ID NOs: 6-21, 32-41, 48-53, and 57-59, wherein the amino acid sequence does not have peptide bonds other than those between the amino acids constituting the amino acid sequence.

[0039] Furthermore, it goes without saying that the deletion of amino acids, substitution, or addition of other amino acids in the cyclic peptide of the present invention may occur independently or simultaneously.

[0040] Furthermore, the above cyclic peptide variants may undergo further deletions, substitutions, or additions of amino acids in the cyclic peptide, as long as they maintain or strengthen their binding to the CNP receptor. The number of such deletions can be, for example, 1, 2, 3, 4, 5, 6, or even more than 6, as long as CNP activity is preserved.

[0041] Furthermore, the amino acid sequence homology resulting from the deletion, substitution, or addition may be 70%, preferably 80%, and more preferably 90% or more homology to the cyclic peptide of the above-mentioned mutant. Moreover, the homology is not limited to this range, as long as activity is maintained.

[0042] Furthermore, as for the substituted amino acids, any amino acid constituting the C-ring peptide of the present invention may be substituted with any other amino acid, as long as the function (activity) of CNP is maintained. The substituted amino acids are glycine, leucine, aspartic acid, isoleucine, glycine, and serine, which constitute the C-ring peptide, and these can be substituted with alanine, methionine, valine, threonine, isoleucine, leucine, and phenylalanine.

[0043] Furthermore, examples of amino acids that can be substituted with other amino acids, in the case of cyclic peptides (formula I), are shown in Tables 27 and 28 below, but are not limited to these.

[0044] Examples of cyclic peptides with one amino acid substitution include, but are not limited to, SEQ ID NOs: 6-21. Examples of cyclic peptides with two amino acid substitutions include, but are not limited to, SEQ ID NOs: 32-41. Examples of cyclic peptides with three amino acid substitutions include, but are not limited to, SEQ ID NOs: 48-53. Examples of cyclic peptides with four amino acid substitutions include, but are not limited to, SEQ ID NOs: 57-59. Furthermore, by appropriately combining the above-mentioned amino acids, five or more amino acids can be substituted in cyclic peptides such as SEQ ID NOs: 1 or 60-62. It should be noted that, in addition to the amino acid sites that may be mutated as described in SEQ ID NOs: 1, other amino acids can also be modified as appropriate.

[0045] Furthermore, the present invention may also be the above-mentioned variants or derivatives thereof. Therefore, any variant or derivative thereof is included in the cyclic peptide according to the present invention, as long as it has the effects of the present invention. In another embodiment, the cyclic peptide may have at least CNP activity. Having CNP activity means having 20% ​​or more binding activity to natriuretic peptide receptors (e.g., GC-A, GC-B). The above CNP activity can be measured according to conventional methods.

[0046] Furthermore, the cyclic peptide of the present invention or the amino acids constituting it may be appropriately modified for the purpose of improving the activity of the cyclic peptide of the present invention, prolonging the effects of the present invention, and / or increasing the storage stability of the cyclic peptide of the present invention. For example, the amino acids of the cyclic peptide of the present invention may be chemically modified, some of the amino acids constituting the cyclic peptide may be deleted, substituted with other amino acids, and / or new amino acids may be added.

[0047] The cyclic peptide of the present invention includes derivatives of the aforementioned cyclic peptide, and such derivatives can be used as active substances or as prodrugs.

[0048] Furthermore, derivatives of the present invention can be obtained by adding (modifying) known substituents to specific groups of amino acids in a cyclic peptide, such as hydrogen atoms, hydroxyl groups, carboxyl groups, amino groups, imino groups, etc., or by substituting them with known substituents that can be substituted. Examples of modifications include, but are not limited to, chemical modifications to amino acids in a cyclic peptide, such as glycosylation, acetylation, phosphorylation, and lipid addition.

[0049] Furthermore, the addition (modification) or substitution of amino acids to the groups in a cyclic peptide may occur simultaneously on one, two or more groups, or even more. Such substituents are not particularly limited to those described below, and any known substituents that can be substituted for the above-mentioned groups can be used. For example, protecting groups such as BOC, as described below, are naturally included.

[0050] Furthermore, for example, by replacing the C-terminal group of one Cys in a cyclic peptide with -COOH, we can create -COOR 1 , -CONHR 1 or -CONR 1 2. Replace the N-terminal group of the other Cys of the cyclic peptide with NH2, -NHC(O)R 1 or -N(C(O)R1 ) can be set to 2. Here, R 1 Each instance is independently a branched or straight-chain hydrocarbon group, alkylene glycol chain, or sugar chain having 1 to 20 carbon atoms. 1 The number of carbon atoms is preferably 1 to 10, more preferably 1 to 5, and even more preferably 1 to 2.

[0051] Furthermore, while not particularly limited, pharmaceutically acceptable salts of the cyclic peptide or derivative of the present invention include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic, neutral, or acidic amino acids. Preferred 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. Preferred examples of salts with organic bases include, for example, 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. Preferred examples of salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. 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, while 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.

[0052] Among the above, a cyclic peptide consisting of the amino acid sequence represented by formula (I) or a pharmaceutically acceptable salt thereof is preferred. That is, the amino acid sequence represented by formula (I) is preferably unsubstituted.

[0053] The method for producing the cyclic peptides, derivatives, and pharmaceutically acceptable salts thereof of the present invention is not particularly limited, and for example, known chemical synthesis methods or genetic engineering synthesis methods can be used.

[0054] When synthesizing the above amino acid sequence by chemical synthesis, any chemical synthesis method may be used, including known peptide synthesis methods such as solid-phase synthesis and liquid-phase synthesis. Furthermore, commercially available peptide synthesizers (e.g., Shimadzu Corporation: PSSM-8) may be used for synthesis.

[0055] Furthermore, the disulfide bonds in the amino acid sequence are not particularly limited, but can be formed by methods such as DMSO oxidation or iodine oxidation. In this case, intramolecular disulfide bonds can be formed by treating free sulfhydryl groups or sulfhydryl groups protected by protecting groups with DMSO or iodine (I2), and as a result, cyclic peptides can be obtained.

[0056] Examples of protecting groups include 4-methylbenzyl group (Bzl(4Me)), trityl group (Trt), tert-butyl group, and N-(acetyl)aminomethyl group (Acm). Deprotection can be carried out by appropriate treatment corresponding to these protecting groups; for example, 4-methylbenzyl group can be treated with a strong acid, and N-(acetyl)aminomethyl group can be treated with iodine.

[0057] Next, the cyclic peptide is derivatized as needed to obtain a derivative. Derivatization can be carried out by known methods. Alternatively, the derivative of the cyclic peptide may be produced along with the peptide synthesis by introducing substituents to the amino acids constituting the cyclic peptide beforehand.

[0058] Next, if necessary, a pharmaceutically acceptable salt is produced by salt exchange of the cyclic peptide or derivative. Salt exchange can be carried out, for example, by contacting the cyclic peptide or derivative with the desired acid or base.

[0059] On the other hand, when synthesizing peptides genetically, they can be synthesized by known methods, such as those 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. The preparation of the DNA fragment can be done, for example, in the case of a DNA fragment encoding the amino acid sequence represented by formula (I), by using a vector containing the full-length human CNP gene as a template and amplifying the DNA fragment by PCR using primers designed to synthesize a predetermined DNA region. Alternatively, the DNA fragment may be synthesized chemically.

[0060] Next, the amplified DNA fragments are ligated into a suitable vector to obtain a recombinant vector for protein expression. Then, 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 by the cells (a protein consisting of the amino acid sequence represented by formula (I)) is recovered. The formation of disulfide bonds, derivatization, and salt formation in the recovered protein can be carried out as described above.

[0061] Furthermore, confirmation that the target compound, such as a cyclic peptide, has been obtained can be performed using known methods such as reversed-phase HPLC or mass spectrometry. Furthermore, the presence or absence of CNP activity in the obtained compounds can be easily confirmed by known means, for example, by testing the cGMP production activity in NPR-B receptor-expressing cells.

[0062] 2. Topical preparations Next, the topical preparation of the present invention will be described. In this invention, the term "topical preparation" simply refers to an preparation applied to the skin or mucous membranes, and is not limited to uses such as pharmaceuticals, quasi-drugs, skincare products, or cosmetics.

[0063] The topical preparation of the present invention comprises one or more cyclic peptides and / or derivatives thereof as described above, and / or pharmaceutically acceptable salts thereof. When two or more cyclic peptides are used, there is no particular upper limit on the types of cyclic peptides to be mixed, but two to three types are preferred from the standpoint of preparation cost and ease of preparation. Examples include SEQ ID NOs. 50, 58, 15, and 9, but the present invention is not limited to these, and these cyclic peptides can be appropriately combined according to the target application, etc., as long as they do not impair the effects of the present invention.

[0064] 2.1 Application The topical preparation of the present invention is not particularly limited, but can be used for the following purposes, for example, and exhibits unprecedented and remarkable effects in each case. Furthermore, the topical preparation of the present invention is not particularly limited in its use and can be used as a pharmaceutical, quasi-drug, and / or cosmetic depending on its pharmacological effects and efficacy.

[0065] The following provides a detailed explanation for each application. (1) Agents for treating dermatitis, agents for preventing dermatitis The topical preparation of the present invention may be a treatment for dermatitis and / or a preventive agent for dermatitis.

[0066] The topical preparation of the present invention, when applied to the skin or mucous membrane of a person suffering from dermatitis, can rapidly alleviate or eliminate various perceptible symptoms and conditions caused or that may occur due to dermatitis, such as itching, pain, heat, tightness, erythema, infiltration, papules, lichenification, crusting, exudation, and dry skin, while also improving objective symptoms of dermatitis. Furthermore, the topical preparation of the present invention does not cause irritation at the application site.

[0067] Furthermore, the effects of the topical preparation containing the cyclic peptide of the present invention are expressed more rapidly and have a longer duration compared to the effects of topical preparations containing CNPs with a tail. The reason for this advantageous effect of the cyclic peptide compared to CNPs is not clear, but it is thought that the cyclic peptide of the present invention has a structure that is more favorable to binding to its receptor, the NPR-B receptor, compared to CNPs. This allows it to bind more rapidly to NPR-B receptors near the affected area, and the binding time is longer. In addition, by binding relatively rapidly to NPR-B receptors near the affected area, it is possible to prevent the cyclic peptide from diffusing outside the affected area via blood flow, etc., and thus keep the cyclic peptide near the affected area for a relatively long period of time.

[0068] Furthermore, the topical preparation of the present invention not only suppresses or prevents inflammation of dermatitis, but also has the effect of restoring or maintaining the skin's barrier function. Here, the skin's barrier function has the function of preventing the invasion of stimuli from the external environment and bacteria into the skin, as well as a moisturizing function. By restoring the barrier function with the topical preparation, the progression and worsening of inflammation can be prevented. The skin's barrier function is greatly influenced by the alignment of keratinocytes in the stratum corneum, i.e., the state of skin texture and the state of moisture. Since the topical preparation of the present invention has the effect of regulating skin texture and moisturizing the skin, the effect of the topical preparation on restoring and maintaining the skin's barrier function is also clear.

[0069] Furthermore, the topical agent of the present invention is also effective against skin conditions such as comedones, erythematous papules, pustules, cysts, and nodules, which are commonly known as acne.

[0070] Furthermore, the rapid improvement or disappearance of perceptible symptoms and conditions reduces the burden on the patient, improves the patient's quality of life, and prevents the patient from damaging the affected area by touching or scratching itchy or painful areas. The effect of the topical preparation of the present invention on the improvement or disappearance of perceptible symptoms and conditions generally occurs within 10 minutes after application, preferably within 5 minutes, and more preferably within 3 minutes.

[0071] In addition, the topical agent of the present invention can treat dermatitis that has resulted from steroid-induced dermatitis, as well as dermatitis that cannot be treated with other common dermatitis treatment agents such as steroids and tacrolimus, for example, dermatitis that does not produce satisfactory therapeutic effects, is resistant to those formulations, or is unsuitable or undesirable for use. Furthermore, conventional topical steroid agents have had a major problem in that when topical use is discontinued, the severity immediately returns to the level before topical use, or a rebound phenomenon occurs, worsening the condition to a level worse than before topical use. However, the topical agent of the present invention does not have such a rebound phenomenon problem.

[0072] Dermatitis is generally a disease that causes inflammation of the skin or mucous membranes. Dermatitis is usually accompanied by acute eczematous symptoms such as erythema, infiltrative erythema, papules, vesicles, pustules, infiltration, crusting, and desquamation; chronic eczematous symptoms such as lichenification and hyperpigmentation; or one or more symptoms selected from the group consisting of scaling, crusting, scratching, scratch marks, prurigo nodules, erosions, edema, oozing, and scaly formation.

[0073] Here, dermatitis is not particularly limited to any disease involving inflammation of the skin or mucous membranes, but includes, for example, eczema such as chronic eczema, dyshidrotic eczema, and infantile xerotic eczema; atopic dermatitis; contact dermatitis such as allergic contact dermatitis and primary irritant contact dermatitis; seborrheic dermatitis; xerosis; 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 eruptions; psoriasis vulgaris, guttate psoriasis, and psoriasis vulgaris. Psoriasis such as erythrodermic tinea, pustular psoriasis, and psoriatic arthritis; prurigo such as chronic prurigo, acute prurigo, prurigo of pregnancy, and prurigo nodularis; rosacea; rosacea-like dermatitis; cutaneous vasculitis such as allergic vasculitis; pruritus such as generalized pruritus, localized pruritus, senile pruritus, and pruritus of pregnancy; photodermatitis; erythroderma; nummular dermatitis; localized scratching dermatitis; perioral dermatitis; dyshidrotic eczema; keratosis pilaris; lichen planus, dyshidrotic eczema, dyhidrosis, miliaria, acne vulgaris, and actinosis are examples of diseases that can be treated and prevented by the topical preparations of the present invention.

[0074] The topical preparation of the present invention exhibits excellent efficacy, particularly against eczema, atopic dermatitis, contact dermatitis, seborrheic dermatitis, insect bites, allergic or non-allergic urticaria, and psoriasis, preferably against eczema, atopic dermatitis, contact dermatitis, insect bites, and actinic dermatitis, and more preferably against eczema and atopic dermatitis. Therefore, the topical preparation of the present invention can be used for the treatment or prevention of at least one dermatitis selected from the above group.

[0075] (2) Materials for cosmetics or skincare products The topical preparation of the present invention can be an ingredient in cosmetics or skincare products. The topical preparation of the present invention, when applied to the skin and / or mucous membranes, moisturizes the application site, exhibiting a moisturizing effect to prevent dryness, as well as preventing rough and sensitive skin. If the stratum corneum is present at the application site, it exhibits an effect of refining the texture of the skin at the application site. In addition, it imparts and maintains appropriate elasticity and flexibility to the skin and mucous membranes, making the skin softer, firmer, and tighter. Furthermore, it improves wrinkles and sagging, including fine and deep wrinkles, at the application site, and also makes dullness and blemishes less noticeable. As a result of the reduction in the appearance of dullness and blemishes, a whitening effect is obtained. Furthermore, it can prevent photosensitivity.

[0076] 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 mucous membranes, for purposes that are not particularly limited, such as preventing the occurrence, progression, or improvement of dry skin, rough skin, sensitive skin, chapped lips, sagging, fine wrinkles and deep wrinkles, as well as for the purpose of maintaining the condition of the skin or mucous membranes, preventing photosensitivity, anti-aging, and whitening, or for the purpose of obtaining at least one effect selected from the above effects. In this specification, skin irritation includes heat rash, chilblains, chapped skin, cracked skin, acne, diaper rash, sores, chafing, and razor burn.

[0077] Specific uses of the external preparation of the present invention as a material for cosmetics or skincare products are not particularly limited, but include, for example, lotions, emulsions, serums, creams, cold creams, gels, masks, packs, powders, hand creams, body powders, aftershave lotions, pre-shave lotions, perfumes, deodorants, as well as makeup cosmetics such as foundations, face powders, eyeshadows, eyeliners, mascaras, eyebrow products, blushes, makeup bases, lipsticks, lip balms, and nail polishes, as well as hair cosmetics such as shampoos, rinses, conditioners, hair colorants, hair tonics, styling agents, and permanent wave treatments, body cleansers such as facial cleansers, makeup removers, body soaps, and hand soaps, and bath additives.

[0078] The effects of the topical preparation of the present invention are rapidly manifested, and although they vary depending on the type of effect, they generally manifest within 10 minutes after application, preferably within 5 minutes, and more preferably within 3 minutes. Furthermore, the effects of the topical preparations of the present invention are relatively long-lasting, and although they vary depending on the type of effect, they generally last for 4 hours or more, preferably 8 hours or more, and more preferably 24 hours or more after the onset of effect.

[0079] (3) Antipruritic agents 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 because, when applied to the skin or mucous membrane, it rapidly exhibits an excellent antipruritic effect at the application site. Furthermore, the antipruritic effect of the topical preparation of the present invention, as described above, generally manifests within 10 minutes after application, preferably within 5 minutes, and more preferably within 3 minutes.

[0080] (4) Hair loss treatment agents, hair loss preventative agents, hair growth agents, hair regrowth agents or hair loss prevention agents Furthermore, the topical preparation of the present invention may be a treatment for alopecia, a preventive agent for alopecia, a hair growth agent, a hair regrowth agent, and / or a hair loss prevention agent. The topical preparation of the present invention, when applied to areas such as areas of hair loss or hair growth, prevents hair loss and shedding in the applied area, promotes hair growth or development, and thickens the hair. Furthermore, it exhibits effects such as hair nourishment, hair growth promotion, and improvement / prevention of thinning hair in the applied area. In this case, the hair that grows tends to be coarse and not gray. Moreover, these effects manifest relatively quickly and are more pronounced compared to other active ingredients used in conventional alopecia treatments, such as CNP.

[0081] Furthermore, as described above, the topical preparation of the present invention has the effect of improving and preventing dermatitis. Therefore, it can improve or prevent skin inflammation associated with alopecia. Such effects are particularly advantageous when alopecia is exacerbated due to the condition of the skin at the application site, such as the scalp.

[0082] Furthermore, as described above, when applied to the skin, the topical preparation of the present invention exhibits moisturizing and skin-texturing effects at the application site. It can remove dandruff and itchiness, suppress their occurrence, moisturize the hair and scalp, improve and prevent dryness, improve seborrheic conditions, and maintain a healthy scalp and hair. It can also improve seborrheic conditions.

[0083] Furthermore, as described above, the topical preparation of the present invention has the effect of alleviating or eliminating perceptible symptoms and conditions. This reduces the burden on the subject (patient) and improves the patient's quality of life. In addition, it can prevent the patient from touching or scratching the affected area, which damages the area, and as a result, it can prevent the worsening of skin conditions that cause alopecia.

[0084] When the topical preparation of the present invention is used as a treatment or preventive agent for alopecia, the applicable alopecia are not particularly limited, but examples include the following types of alopecia, and it can be used for the treatment or prevention of one or more of these types.

[0085] (Acquired alopecia) (i) Alopecia without scarring or skin lesions (alopecia areata, male pattern baldness, seborrheic alopecia, pityriasis versicolor, female pattern baldness, pregnancy alopecia, malignant alopecia, senile alopecia, frontal alopecia, multiple alopecia, serpentine alopecia, drug-induced alopecia, cancer chemotherapy-induced alopecia and radiation-induced alopecia, traumatic / mechanical alopecia, alopecia associated with nutritional / metabolic disorders, alopecia associated with endocrine disorders, telogen effluvium (postpartum alopecia, post-hypertensive alopecia))

[0086] (ii) Alopecia seen in skin lesions or diseased skin (alopecia due to infection, alopecia due to tumor, alopecia due to inflammation) (iii) Scarring alopecia (hair loss due to skin infection, hair loss due to inflammatory cell infiltration)

[0087] (Congenital alopecia) Diffuse alopecia, congenital alopecia, alopecia in hereditary syndromes, localized alopecia, nevus alopecia, aplasia cutis, congenital triangular alopecia

[0088] Among those described above, the topical preparation of the present invention exhibits excellent effects particularly against acquired alopecia, preferably against alopecia without scarring or skin lesions, and more preferably against alopecia areata, male pattern baldness, seborrheic alopecia, pityriasis versicolor, female pattern baldness, pregnancy alopecia, malignant alopecia, senile alopecia, frontal alopecia, multiple alopecia, serpentine alopecia, drug-induced alopecia, cancer chemotherapy-induced alopecia, radiation exposure-induced alopecia, traumatic / mechanical alopecia, alopecia associated with nutritional / metabolic disorders, alopecia associated with endocrine abnormalities, and telogen effluvium. Therefore, the topical preparation of the present invention can be used for the treatment or prevention of at least one type of alopecia selected from the above group.

[0089] (5) Rhinitis treatments and / or rhinitis preventives Furthermore, the topical preparation of the present invention may be a rhinitis treatment agent and / or a rhinitis preventive agent. Rhinitis is a disease caused by inflammation of the mucous membrane of the nasal cavity and / or paranasal sinuses, and in addition to the main symptoms of nasal congestion, runny nose, and sudden, recurrent sneezing, it can also cause symptoms such as itching. In this invention, "rhinitis" includes not only rhinitis involving inflammation of the nasal cavity mucosa in the narrow sense, but also sinusitis involving inflammation of the paranasal sinus mucosa.

[0090] When applied to the nasal mucosa and / or paranasal sinus mucosa, the topical preparation of the present invention can improve or prevent various symptoms associated with rhinitis, such as nasal congestion, rhinorrhea, sneezing, and itching. In particular, these effects appear more rapidly and last longer compared to rhinitis treatments containing CNPs with tails.

[0091] The effect of the topical preparation of the present invention on rhinitis generally appears within 8 minutes after application, preferably within 5 minutes, and more preferably within 3 minutes. Even more preferably, it appears within 1 minute. Furthermore, the effect of the topical preparation 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 effect.

[0092] When the topical preparation of the present invention is used as a treatment and / or preventive agent for rhinitis, the applicable rhinitis is not particularly limited and includes, for example, infectious rhinitis including acute rhinitis and chronic rhinitis; hypersensitive non-infectious rhinitis including complex (pollen hypersensitivity) rhinitis, runny nose rhinitis, congestive rhinitis, edematous rhinitis, and dry rhinitis; irritant rhinitis including physical rhinitis, chemical rhinitis, and radiation rhinitis; as well as atrophic rhinitis and characteristic granulomatous rhinitis; and sinusitis such as acute sinusitis, chronic sinusitis (chronic sinusitis), eosinophilic sinusitis, and sinus mycosis. It can be used for the treatment or prevention of one or more of the above.

[0093] Furthermore, complex rhinitis includes, for example, allergic rhinitis, which encompasses perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis, which encompasses vasomotor (essential) rhinitis and eosinophilic rhinitis. Examples of rhinitis with runny nose include gustatory rhinitis, cold-inhalation rhinitis, and senile rhinitis.

[0094] Examples of congestive rhinitis include drug-induced rhinitis, psychogenic rhinitis, pregnancy-related rhinitis, endocrine rhinitis, and cold-induced rhinitis. An example of edematous rhinitis is aspirin-sensitive rhinitis.

[0095] Among those described above, the topical preparation of the present invention exhibits particularly excellent effects against hypersensitive non-infectious rhinitis, irritant rhinitis, and sinusitis, preferably against hypersensitive non-infectious rhinitis and chronic sinusitis, and more preferably against complex (nasal hypersensitivity) rhinitis, rhinorrhea, congestive rhinitis, edematous rhinitis, and dry rhinitis, and chronic sinusitis. Therefore, the topical preparation of the present invention can be used for the treatment or prevention of at least one type of rhinitis selected from the above group.

[0096] Furthermore, from a symptomatic standpoint, the topical preparation of the present invention has the effects described above and can therefore be used for any of the following types of rhinitis: sneezing-and-runny-overhead rhinitis, nasal congestion rhinitis, and complete rhinitis. Furthermore, the topical preparation of the present invention shows symptom improvement effects even in rhinitis that is difficult to treat with conventionally used rhinitis treatments such as steroid drugs.

[0097] (6) Other topical preparations Furthermore, the topical preparation of the present invention can be used for purposes other than those described above, for the purpose of achieving the effects of the cyclic peptide described above. In this case, the topical preparation of the present invention may primarily aim for effects other than those of the cyclic peptide described above. In this case, the cyclic peptide of the present invention, its derivatives and / or pharmaceutically acceptable salts are used for the purpose of assisting the main effect of the topical preparation or adding effects other than the main effect.

[0098] Such uses are not limited to, but include, for example, deodorizing, antiperspirant, hair removal, cleansing, promoting blood circulation and fragrance, preventing UV damage, UV protection, sterilization, antiseptic, antioxidant, and promoting transdermal absorption.

[0099] 2.2 Dosage Forms The topical preparation of the present invention, when administered locally to a target site (e.g., the affected area) of the skin or mucous membrane, allows the effects of the active ingredient, a cyclic peptide, its derivatives, and / or pharmaceutically acceptable salts, to be expressed more reliably and rapidly near the application site. Such topical preparations are not particularly limited, but may include, for example, dermal preparations, eye drops, ear drops, nasal drops, oral preparations, or suppositories. Of these, if the topical preparation of the present invention is a dermatitis treatment agent, dermatitis preventive agent, antipruritic agent, skin care product, alopecia treatment agent, alopecia preventive agent, hair growth agent, or hair regrowth agent, it is preferably a dermal preparation. On the other hand, if the topical preparation of the present invention is a rhinitis treatment agent and / or rhinitis preventive agent, it is preferably a nasal drop. Furthermore, if it is a corneal disease treatment and / or preventive agent, it is preferably an eye drop.

[0100] The topical preparation of the present invention, when it is a topical preparation, is not particularly limited, but may be, for example, a topical solid preparation, a topical liquid preparation, a spray preparation, an ointment preparation, an emulsion, a cream preparation, a gel preparation, or a patch preparation.

[0101] Topical solid preparations are solid formulations intended for application or spraying onto the skin or other surfaces. Examples of such topical solid preparations include powdered topical preparations. Topical solutions are liquid preparations intended for application to the skin or other surfaces. Examples of such topical solutions include lotions and liniments.

[0102] A spray is a formulation that sprays the active ingredient onto the skin in the form of a mist, powder, foam, or paste. Examples of such sprays include topical aerosols and pump sprays. Ointments are semi-solid preparations applied to the skin, in which an active ingredient is dissolved or dispersed in a base. Ointments may also be lip balms applied to local areas such as the lips. A cream is a semi-solid formulation that is emulsified into an oil-in-water or water-in-oil type and applied to the skin.

[0103] Gel formulations are gel-like preparations applied to the skin. Examples of gel formulations include aqueous gel formulations and oil-based gel formulations. Patches are preparations applied to the skin. Examples of patches include tapes and poultices. Nasal sprays are preparations administered into the nasal cavity or nasal mucosa. Examples of nasal sprays include nasal powders and nasal liquids. Of these, nasal liquids are preferred.

[0104] In any of the above-described dosage forms, the topical preparation of the present invention comprises at least the cyclic peptides and / or derivatives thereof of the present invention as described above, and / or pharmaceutically acceptable salts thereof.

[0105] When the dosage form is a topical solution, ointment, cream, or gel, the topical preparation of the present invention contains cyclic peptides and / or derivatives thereof and / or pharmaceutically acceptable salts thereof at concentrations, 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, it may contain at concentrations of 0.1 to 800 μg / g or 1 to 500 μg / g.

[0106] Furthermore, when the dosage form is a spray, the topical preparation of the present invention contains, in the stock solution of the spray, cyclic peptides and / or derivatives thereof and / or pharmaceutically acceptable salts thereof at concentrations, 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, it may also contain at concentrations of 0.1 to 800 μg / mL and 1 to 500 μg / mL.

[0107] When the dosage form is a patch, the topical preparation of the present invention contains cyclic peptides and / or derivatives thereof and / or pharmaceutically acceptable salts thereof at concentrations 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0108] Furthermore, when the dosage form is a nasal spray, particularly a liquid nasal spray, the topical preparation of the present invention contains, in the liquid (nasal solution) of the nasal spray, cyclic peptides and / or derivatives thereof, and / or pharmaceutically acceptable salts thereof, at concentrations of, for example, 0.001 to 10000 μg / mL, more preferably 0.01 to 1000 μg / mL, more preferably 0.1 to 100 μg / mL, and even more preferably 1 to 100 μg / mL. In another embodiment, it may also contain at concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0109] Regardless of which dosage form the present invention is, the topical preparation can be formulated using methods and constituent materials known to those skilled in the art.

[0110] The available constituent materials are not particularly limited, but examples include thickening and gelling agents, oily components, alcohols, fatty acids, organic acids, UV absorbers, UV scattering agents, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, chelating agents, fragrances, preservatives, and animal and plant extracts.

[0111] Various organic and inorganic gelling agents can be used as thickening and gelling agents. Examples of gelling agents for inorganic compounds include water-containing or water-absorbing silicates, such as aluminum silicate (e.g., bentonite), magnesium aluminum silicate, and colloidal silica. Natural, semi-synthetic, or synthetic polymers can be used as gelling agents for organic compounds. 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 alkylcellulose (e.g., methylcellulose or ethylcellulose), and carboxy- or hydroxy-lower alkylcellulose (e.g., carboxymethylcellulose or hydroxypropylcellulose). Examples of synthetic polymers include carboxyvinyl polymer, sodium polyacrylate, (vinyl methyl ether / ethyl maleate) copolymer, polymethacrylate, polyvinyl alcohol, polyvinylpyrrolidone, polyacrylic acid, or polymethacrylic acid. Commercial gelling agents such as Rubragel NP, Rubragel CG, Rubragel DV, Rubragel MS, Rubragel OIL, Rubragel TW, Rubragel DS (Ashland) can also be used as gelling agents.

[0112] As for the oil component, for example, various oil phase components such as ester-based, ether-based, hydrocarbon-based, silicone-based, and fluorine-based oils can be used, as well as animal and vegetable oils and their hydrogenated oils, and naturally derived waxes.

[0113] 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, diethyl sebacate, diisopropyl adipate, isoarachil neopentanoate, caprylic / capric triglyceride, trimethylolpropane tri-2-ethylhexanoate, trimethylolpropane triisostearate, pentaerythritol tetra-2-ethylhexanoate, cetyl caprylate, decyl laurate, and hexyl laurate. Decyl myristate, myristyl myristate, cetyl myristate, stearyl stearate, decyl oleate, cetyl ricinoleate, isostearyl laurate, isotridecyl myristate, isocetyl myristate, isostearyl myristate, 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, di(caprylic / capric acid)propylene glycol, propylene glycol dicaprylate, neopentyl glycol dicaprate, neopentyl glycol dioctanoate,

[0114] 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 (C12-18) carbonate, triisocetyl citrate, triisoarachil citrate, triisooctyl citrate, lauryl lactate, myristyl lactate, cetyl lactate, octyldecyl lactate, triethyl citrate, Examples include acetyltriethyl citrate, acetyltributyl 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.

[0115] Examples of hydrocarbon-based oil phase components include squalane, liquid paraffin, α-olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, solid paraffin, polybutene, microcrystalline wax, and petrolatum.

[0116] Examples of silicone-based oil phase components include dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organopolysiloxane, dimethylsiloxane-methylcetyloxysiloxane copolymer, dimethylsiloxane-methylstearoxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, silicone gel, acrylic silicone, trimethylsiloxysilicate, and silicone RTV rubber. Examples of fluorine-based oil phase components include perfluoropolyethers, fluorine-modified organopolysiloxanes, fluorinated pitch, fluorocarbons, fluoroalcohols, and fluoroalkyl / polyoxyalkylene copolymerized organopolysiloxanes.

[0117] Examples of animal and vegetable oils and their hydrogenated oils, as well as naturally derived waxes, include, for example, 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, as well as avocado oil, almond oil, olive oil, cocoa 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. Examples include 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, meadow humme oil, cottonseed oil, hydrogenated cottonseed oil, coconut oil, hydrogenated coconut oil, rosehip oil, and other vegetable oils and their hydrogenated oils, as well as beeswax, high-acid value beeswax, lanolin, reduced lanolin, hydrogenated lanolin, liquid lanolin, carnauba wax, montan wax, and other waxes.

[0118] 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.

[0119] 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, arachidic acid, arachidonic acid, behenic acid, erucic acid, and 2-ethylhexanoic acid.

[0120] Examples of UV absorbers include para-aminobenzoic acid, amyl para-aminobenzoate, ethyl dihydroxypropyl para-aminobenzoate, glyceryl para-aminobenzoate, ethyl para-aminobenzoate, octyl para-aminobenzoate, octyl dimethyl para-aminobenzoate, ethylene glycol salicylate, octyl salicylate, triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomentyl salicylate, benzyl cinnamate, octyl para-methoxycinnamate, 2-ethylhexyl para-methoxycinnamate, glyceryl mono-2-ethylhexanoate dipara-methoxycinnamate, isopropyl para-methoxycinnamate, diethanolamine para-methoxyhydrocinnamate salt, diisopropyl / diisopropyl cinnamic acid ester mixture, urocanic acid, ethyl urocanic acid, hydroxymethoxybenzophenone, hydroxymethoxybenzophenone sulfonic acid and its salts, dihydro Examples include roxymethoxybenzophenone, sodium dihydroxymethoxybenzophenone disulfonate, dihydroxybenzophenone, dihydroxydimethoxybenzophenone, hydroxyoctoxybenzophenone, tetrahydroxybenzophenone, butylmethoxydibenzoylmethane, 2,4,6-trianilino-p-(carbo-2-ethylhexyl-1-oxy)-1,3,5-triazine, 2-(2-hydroxy-5-methylphenyl)benzotriazole, methyl-O-aminobenzoate, 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, etc., as well as polymer derivatives and silane derivatives thereof, titanium dioxide, zinc oxide and their dispersions, etc. Furthermore, zinc oxide, titanium oxide, etc., may be surface-treated.

[0121] Examples of transdermal 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.

[0122] Powders and pigments include, for example, pigments such as Red No. 104, Red No. 201, Yellow No. 4, Blue No. 1, Black No. 401, basic dyes, HC colors, disperse dyes, 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, polymers such as polyethylene powder, yellow iron oxide, red iron oxide, black iron oxide, chromium oxide, carbon black, ultramarine, Prussian blue, and other colored pigments, oxidation Examples include white pigments such as zinc, titanium dioxide, 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 restrictions on the shape (spherical, rod-shaped, needle-shaped, plate-shaped, irregular shape, flake-shaped, spindle-shaped, etc.) and particle size of these powders.

[0123] These powders and pigments may be pre-treated by conventional surface treatments, such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil treatment, N-acylated lysine treatment, polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment, etc.

[0124] Any of the following surfactants can be used as appropriate: anionic surfactants, cationic surfactants, amphoteric surfactants, and nonionic surfactants. Examples of anionic surfactants include fatty acid soaps, α-acyl sulfonates, alkyl sulfonates, alkylallyl sulfonates, alkylnaphthalene sulfonates, alkyl sulfates, POE alkyl ether sulfates, alkylamide sulfates, alkyl phosphates, POE alkyl phosphates, alkylamide phosphates, alkylylalkyl taurates, N-acyl amino acid salts, POE alkyl ether carboxylates, alkyl sulfosuccinates, alkyl sulfoacetate sodium, acylic acid isethionates, acylated hydrolyzed collagen peptides, and perfluoroalkyl phosphate esters.

[0125] Examples of cationic surfactants include alkyltrimethylammonium chloride, stearyltrimethylammonium chloride, stearyltrimethylammonium bromide, cetostearyltrimethylammonium chloride, distearyldimethylammonium chloride, stearyldimethylbenzylammonium chloride, behenyltrimethylammonium bromide, benzalkonium chloride, beheninamidepropyldimethylhydroxypropylammonium chloride, diethylaminoethylamide stearate, dimethylaminopropylamide stearate, and quaternary ammonium salts of lanolin derivatives. Tertiary amines such as fatty acid amide dialkylamines and their salts are also examples.

[0126] Examples of amphoteric surfactants include various amphoteric surfactants of the carboxybetaine type, amidebetaine type, sulfobetaine type, hydroxysulfobetaine type, amidesulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, and amideamine 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 sorbitan 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 lauric acid alkanolamides, 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.

[0127] 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 sugars, sulfated trehalose, pullulan, and the like. Chemically modified versions of these can also be used.

[0128] Examples of polymers include acrylic acid ester / methacrylic acid ester copolymers, vinyl acetate / crotonic acid copolymers, vinyl acetate / crotonic acid / vinyl neodecanate copolymers, methyl vinyl ether maleate half-ester, T-butyl acrylate / ethyl acrylate / methacrylic acid copolymer, vinylpyrrolidone / vinyl acetate / vinyl propionate copolymer, vinyl acetate / crotonic acid copolymer (Rubyset CA: manufactured by BASF), vinyl acetate / crotonic acid / vinylpyrrolidone copolymer, vinylpyrrolidone / acrylate copolymer, acrylate / acrylamide copolymer, vinyl acetate / butyl maleate / isobornyl acrylate copolymer, carboxyvinyl polymer, acrylic acid Examples include anionic polymer compounds such as lylic acid-alkyl methacrylate copolymers, amphoteric polymer compounds such as dialkylaminoethyl methacrylate polymers, octylacrylamide acrylate / hydroxypropyl acrylate / butylaminoethyl methacrylate copolymers, cationic polymer compounds such as vinylpyrrolidone / dimethylaminoethyl methacrylate quaternaries and methylvinylimidazolium chloride / vinylpyrrolidone copolymers, and nonionic polymer compounds such as polyvinylpyrrolidone, vinylpyrrolidone / vinyl acetate copolymers, vinylpyrrolidone / dimethylaminoethyl methacrylate copolymers, and vinylcaprolactam / vinylpyrrolidone / dimethylaminoethyl methacrylate copolymers. Furthermore, naturally derived high molecular weight compounds such as cellulose or its derivatives, keratin and collagen or their derivatives, calcium alginate, pullulan, agar, gelatin, tamarind seed polysaccharides, xanthan gum, carrageenan, high methoxyl pectin, low methoxyl pectin, guar gum, acacia gum, crystalline cellulose, arabinogalactan, karaya gum, tragacanth gum, alginic acid, albumin, casein, curdlan, gellan gum, and dextran, as well as gluco-oligosaccharides, fucose-containing polysaccharides, and rhamnose-containing polysaccharides can also be suitably blended.

[0129] Bioactive ingredients include substances that provide some kind of physiological activity to the skin when applied to it. For example, these are ingredients that have effects such as whitening, anti-inflammatory, anti-aging, UV protection, slimming, firming, antioxidant, hair growth, hair growth suppression, moisturizing, blood circulation promotion, antibacterial / sterilizing, cooling / warming sensation, wound healing promotion, irritation relief, pain relief, and cell activation. Examples include plant extracts, seaweed extracts, vitamins and their derivatives, amino acids, various peptides other than cyclic peptides, biopolymers such as sodium hyaluronate and mucopolysaccharides, intercellular lipid components or similar components such as ceramides, phytosphingosine, cholesterol, and phytosterols, and enzyme components. Examples of suitable ingredients include, for example, Angelica keiskei extract, avocado extract, Hydrangea macrophylla extract, Althaea officinalis extract, Arnica montana extract, Aloe vera extract, Apricot extract, Apricot kernel extract, Isoflavones, Ginkgo biloba extract, Fennel extract, Turmeric extract, Oolong tea extract, Rosa multiflora extract, Echinacea leaf extract, Scutellaria baicalensis extract, Phellodendron amurense extract, Coptis japonica extract, Barley extract, Hypericum perforatum extract, Lamium album extract, Nasturtium officinale extract, Orange extract, Cocoa extract, Dried seawater, and Seaweed extract. Hydrolyzed elastin, hydrolyzed wheat powder, hydrolyzed silk, pumpkin seed extract, chamomile extract, carrot extract, Artemisia capillaris extract, licorice extract, carrot extract, cinchona extract, cucumber extract, guanosine, gardenia extract, bamboo grass extract, Sophora flavescens extract, cranberry extract, walnut extract, grapefruit extract, clematis extract, chlorella extract, mulberry extract, gentian extract, black tea extract, yeast extract, burdock extract, rice bran fermentation extract,

[0130] Rice germ oil, comfrey extract, collagen, lingonberry extract, asarum extract, bupleurum extract, umbilical cord extract, salvia extract, soapwort extract, bamboo extract, hawthorn extract, sansho 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, geranium extract Toko extract, yarrow extract, peppermint extract, sage extract, mallow extract, Cnidium officinale extract, Swertia japonica extract, soybean extract, jujube extract, fermented soybean extract, thyme extract, tea extract, clove extract, cogongrass extract, citrus peel extract, evening primrose extract, centella asiatica extract, terminalia extract, angelica extract, calendula extract, peach kernel extract, spruce extract, Houttuynia cordata extract, tomato extract, natto extract, Examples of extracts include carrot extract, garlic extract, wild rose extract, hibiscus extract, Ophiopogon extract, parsley extract, honey, banana flower extract, witch hazel extract, parietaria extract, Isodon japonicus extract, bisabolol, loquat extract, coltsfoot extract, butterbur extract, Poria cocos extract, 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, lemon balm extract, peach extract, cornflower extract, eucalyptus extract, saxifrage extract, yuzu extract, coix seed extract, mugwort extract, lavender extract, apple extract, lychee extract, lettuce extract, lemon extract, astragalus extract, rose extract, rosemary extract, Roman chamomile extract, royal jelly extract, etc.

[0131] Furthermore, it contains biopolymers such as deoxyribonucleic acid, mucopolysaccharides, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, and hydrolyzed eggshell membrane; moisturizing ingredients such as amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidone carboxylate, betaine, whey, trimethylglycine, and polypeptides such as lysine-arginine condensate; and intercellular lipid components or similar substances such as sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, phytosterol derivatives, and phospholipids. Anti-inflammatory agents such as ε-aminocaproic acid, glycyrrhizic acid, β-glycyrrhetinic acid, lysozyme chloride, guaiazulene, hydrocoltisone, 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; vitamins such as calcium pantothenate, biotin, and nicotinamide; active ingredients such as allantoin, diisopropylamine dichloroacetate, and 4-aminomethylcyclohexanecarboxylic acid; tocopherol, caro Antioxidants such as tinoids, flavonoids, tannins, lignans, and saponins; 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; whitening agents such as arbutin, kojic acid, placenta extract, sulfur, ellagic acid, linoleic acid, tranexamic acid, and glutathione; cepharanthine, licorice extract, capsicum tincture, hinokitiol, garlic iodide extract, pyridoxine hydrochloride, DL-α-tocopherol, DL-α-tocopherol acetate, nicotinic acid, and Cotinic acid derivatives, calcium pantothenate, D-pantothenyl alcohol, acetyl pantothenyl ethyl ether, biotin, allantoin, isopropylmethylphenol, estradiol, ethinylestradiol, capronium chloride, benzalkonium chloride, diphenhydramine hydrochloride, tacanal, camphor, salicylic acid, vanillyl nonyl acid, 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, hydrocoltisone, minoxidil, polyoxyethylene sorbitan monostearate, peppermint oil, and Sasanishiki extract.

[0132] Examples of antioxidants include sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tol biguanide, nordihydroguaiaretinic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxytoluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoids, flavonoids, tannins, lignans, saponins, and plant extracts with antioxidant effects such as apple extract and clove extract.

[0133] Examples of solvents include physiological saline, purified water, ethanol, lower alcohols, ethers, LPG, fluorocarbons, N-methylpyrrolidone, fluoroalcohols, volatile linear silicones, and next-generation chlorofluorocarbons.

[0134] Furthermore, since the cyclic peptides and / or derivatives thereof and / or pharmaceutically acceptable salts thereof 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 peptides and / or derivatives thereof and / or pharmaceutically acceptable salts thereof of the present invention for the manufacture of topical preparations.

[0135] 3. How to use topical medications Next, the method of using the topical preparation of the present invention will be described. A method of using the topical preparation of the present invention includes applying the topical preparation of the present invention described above to the target skin and / or mucous membrane.

[0136] The subjects are not particularly limited, but examples include vertebrates such as birds and mammals. In particular, mammals include rodents such as mice, rats, gerbils, hamsters, and guinea pigs, laboratory animals such as rabbits, livestock such as pigs, cows, goats, horses, sheep, and mink, pets such as dogs and cats, and primates such as humans, monkeys, crab-eating macaques, rhesus macaques, marmosets, orangutans, and chimpanzees. Among these, humans are particularly preferred. On the other hand, humans can also be excluded from the subjects.

[0137] Furthermore, the skin and / or mucous membranes to which the topical agent is applied may be any part of the body, such as the head (scalp), face, neck, arms, torso, hands, feet, etc. A more specific method of using the topical preparation of the present invention is as follows.

[0138] (1) Treatment and prevention methods for dermatitis When the topical preparation of the present invention is used as a treatment or preventive agent for dermatitis, the topical preparation can be applied directly to the target skin and / or mucous membrane area (for example, the affected area where dermatitis has developed).

[0139] The frequency of application is not particularly limited, but for example, it is 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Furthermore, because the topical preparation of the present invention has a long duration of effect, it exhibits sufficient efficacy even when applied relatively infrequently, for example, once a day. The dosage is also not particularly limited, but for example, the total amount of the cyclic peptide and its derivatives of the present invention and their pharmaceutically acceptable salts per application can be 0.0001 to 1000000 μg / mL, preferably 0.001 to 10000 μg / mL, more preferably 0.01 to 1000 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0140] (2) Methods to reduce or eliminate itching When the topical preparation of the present invention is used as an antipruritic, the topical preparation can be applied directly to the target skin and / or mucous membrane area. The frequency of application is not particularly limited, but for example, it is 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Furthermore, while the dosage is not particularly limited, for example, the total amount of the cyclic peptide and its derivatives of the present invention and their pharmaceutically 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0141] (3) How to use cosmetics When the topical preparation of the present invention is used as a cosmetic, it can be applied directly to the target skin and / or mucous membrane area. The frequency of application is not particularly limited, but for example, it is 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Furthermore, while the dosage is not particularly limited, for example, the total amount of the cyclic peptide and its derivatives of the present invention and their pharmaceutically 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0142] (4) Methods for the treatment and prevention of alopecia, as well as methods for promoting hair growth and hair restoration. When the topical preparation of the present invention is used as a treatment for alopecia, a preventive agent for alopecia, a hair growth agent or hair restoration agent, and / or a method for preventing hair loss, the topical preparation can be applied directly to the target area (for example, the scalp or areas of hair loss on the skin).

[0143] The frequency of application is not particularly limited, but for example, it is 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Furthermore, while the dosage is not particularly limited, for example, the total amount of the cyclic peptide and its derivatives of the present invention and their pharmaceutically 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0144] (5) Treatment and prevention methods for rhinitis When the topical preparation of the present invention is used as a treatment or preventative agent for rhinitis, it can be applied directly to the target area (e.g., the nasal mucosa). The frequency of application is not particularly limited, but for example, it is 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day. Furthermore, while the dosage is not particularly limited, for example, the total amount of the cyclic peptide and its derivatives of the present invention and their pharmaceutically acceptable salts per nasal cavity per application may be preferably 0.001 to 10000 μg / mL, more preferably 0.01 to 1000 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 concentrations of 0.1 to 800 μg / mL or 1 to 500 μg / mL.

[0145] 4. Pharmaceuticals Next, the pharmaceutical product of the present invention will be described. The pharmaceutical product of the present invention comprises one or more cyclic peptides of the present invention or derivatives thereof, or pharmaceutically acceptable salts thereof.

[0146] As described above, the cyclic peptides or derivatives thereof of the present invention, or pharmaceutically acceptable salts thereof, are thought to bind to the receptor NPR-B having a guanylate cyclase domain, similar to CNP, to promote the production of cGMP, and thus have effects such as diuretic effects, vasodilatory effects, inhibition of renin and aldosterone secretion, sympathetic nerve inhibition, and inhibition of hypertrophy. Furthermore, these compounds of the present invention are thought to have superior pharmacological efficacy, efficacy, and especially superior rapid onset of action compared to CNP.

[0147] Therefore, the pharmaceutical product of the present invention can be used for the same purposes as conventional pharmaceutical products containing CNP as an active ingredient. The diseases to which the pharmaceutical product of the present invention can be applied are not particularly limited, but include, for example, the various diseases mentioned above, as well as hypertension, unstable angina, acute myocardial infarction, edematous diseases, renal failure, heart failure, immune diseases, obesity, metabolic syndrome, and the like.

[0148] Furthermore, the dosage form of the pharmaceutical product of the present invention is not particularly limited, and in addition to the topical preparations described above, it can be, for example, oral preparations such as tablets, capsules, granules, powders, oral liquids, syrups, and oral jellies; oral preparations such as oral tablets, oral sprays, semi-solid oral preparations, and mouthwashes; injectable preparations such as injectables and intravenous solutions; dialysis preparations such as dialysis agents; inhalants, eye drops, eye ointments, ear drops, vaginal tablets, and vaginal suppositories. Examples

[0149] The present invention will be described in more detail below with reference to examples. However, the present invention is not limited to these examples.

[0150] 1. Production of cyclic peptides First, a cyclic peptide consisting of the amino acid sequence represented by formula I was synthesized. Specifically, using a peptide synthesizer, amino acids were sequentially linked by solid-phase peptide synthesis to form a linear peptide consisting of 17 amino acids. Subsequently, the protecting groups at the 1st and 17th Cys from the N-terminus were removed. Then, iodine (I2) treatment was performed to oxidatively form cysteine ​​bonds between the same amino acid residues, thereby forming a cyclic peptide. The resulting 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.

[0151] Furthermore, the obtained cyclic peptide was subjected to mass spectrometry. 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 Analytical method: Ion trap method

[0152] As a result, m / z = 878.41([M+2H] 2+ ), m / z = 878.41([M+H] + ) was observed, and the above peptide has the composition formula (C) of the target cyclic peptide. 74 H 123 N 21 O 22 It was confirmed that the molecular weight (1755.10) and mass number (1753.8314) matched the theoretical values ​​calculated from S3).

[0153] 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: 20-40% Eluent B / 20 min Flow rate: 1.2ml / min Temperature: room temperature Injection volume: 20μl Detector: UV detector (detection wavelength 215 nm) The measurement results confirmed that the purity of the obtained protein was 99.2%.

[0154] 2. Manufacturing of pharmaceutical products 2.1 Manufacturing of Gel Formulations A gel-based formulation containing a cyclic peptide consisting of an amino acid sequence represented by formula I (in the following examples, "C-ring" refers to the cyclic peptide represented by formula I) (C-ring gel formulation, example) and a gel-based formulation containing human CNP (CNP gel formulation, comparative example) were prepared as follows. 0.1g of methyl parahydroxybenzoate (product name: Mekkins M, manufactured by Ueno Pharmaceutical Co., Ltd.), 0.2g of phenoxyethanol, and 3.0g of 1,2-pentanediol were weighed into the same container, heated to 60-70°C to form a homogeneous solution, and then added to a mixing kettle. Next, 6.0 g of concentrated glycerin was added to the mixing vessel, and then a mixture of 0.44 g of carboxyvinyl polymer (product name: Carbopol 940, manufactured by Lubrizol Advanced Materials) and 0.08 g of xanthan gum (product name: Keltrol T, manufactured by CP KELCO) was added and stirred with a paddle until thoroughly dispersed.

[0155] Next, 83.95g of purified water was gradually added while stirring with a paddle, and the kettle temperature was heated to 70-80°C. The mixture was stirred with a paddle and a discerning tool to dissolve the dispersed contents and obtain a solution. After that, the discerning tool was stopped, and cooling was immediately started after confirming that the contents in the solution had dissolved. When the kettle temperature reached approximately 40°C, 6.0g of Ashland's Rubragel NP (2.7g glycerin, 0.06g carboxyvinyl polymer, 0.018g sodium polyacrylate, 3.222g water) was added to the solution and mixed uniformly with a paddle. Subsequently, 0.230g 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 the gel base.

[0156] Next, 17 μl of a C-ring solution obtained by dissolving 1 mg of a cyclic peptide (C-ring) consisting of the amino acid sequence represented by formula II in 1 mL of purified water was uniformly mixed with 10 g of the gel base obtained above to produce a gel base formulation (C-ring gel formulation) with a C-ring concentration of approximately 1 μM (approximately 1.7 μg / g). Similarly, gel base formulations with C-ring concentrations of approximately 2.0 μM (approximately 3.4 μg / g) and approximately 5.0 μM (approximately 8.5 μg / g) were produced. In the following examples, unless otherwise specified, the "C-ring gel formulation" used had a C-ring concentration of approximately 1 μM. Next, 22 μl of a CNP solution obtained by dissolving 1 mg of human CNP-22 (American Peptide Company) in 1 mL of purified water was uniformly mixed with 10 g of the gel base obtained above to produce a gel base formulation (CNP gel formulation) with a CNP-22 concentration of approximately 1 μM. In the same manner, gel base formulations with CNP-22 concentrations of approximately 2.0 μM and 5.0 μM were produced. In the following examples, unless otherwise specified, the "CNP gel formulation" used had a CNP concentration of approximately 1 μM.

[0157] 2.2 Manufacturing of nasal sprays A nasal spray containing a cyclic peptide (C-ring) consisting of an amino acid sequence represented by formula II (C-ring nasal spray, example) and a nasal spray containing human CNP (CNP nasal spray, comparative example) were prepared as follows.

[0158] First, a cyclic peptide (C-ring) consisting of the amino acid sequence represented by formula II was dissolved in physiological saline, and the concentration was adjusted to obtain a C-ring nasal spray with a C-ring concentration of approximately 1 μmol / l (approximately 1.7 μg / g). Next, the C-ring nasal solution was filled into a quantitative nasal spray container (manufactured by AS ONE Corporation), and the amount of spray per use was adjusted to 100 μl (0.1 ml) to obtain the C-ring nasal spray.

[0159] Similarly, for human CNP (American Peptide Company), a CNP nasal spray with a CNP concentration of 1 μmol / l (μM) was obtained, which was then filled into a quantitative nasal spray container (manufactured by AS ONE Corporation), and the amount of spray per application was adjusted to 100 μl (0.1 ml) to obtain the CNP nasal spray.

[0160] 3. Confirmation of the effectiveness of dermatitis treatment. 3.1 Confirmation of the efficacy of C-ring gel formulations In subjects suffering from various types of dermatitis, the C-ring gel formulation described above was applied to the affected area, and changes in symptoms before and after application were observed. Where possible, as a comparative example, the same subjects were also given the CNP gel formulation described above to the affected area where the C-ring gel formulation had not been applied, and changes in symptoms before and after application were observed. Itching was evaluated on a 10-point scale using a Visual Analogue Scale (VAS) for each affected area. The test results, along with the age, sex, symptoms, and prescriptions given to the subjects, are shown in the table below.

[0161] [Table 1]

[0162] [Table 2]

[0163] [Table 3]

[0164] [Table 4]

[0165] [Table 5]

[0166] [Table 6]

[0167] As shown in the table above, in all subjects, regardless of the type of dermatitis, improvement or disappearance of various dermatitis symptoms was observed at the site where the C-ring gel formulation was applied. In particular, when the C-ring gel formulation was applied, a reduction or disappearance of itching was observed immediately after application. In dermatitis, patients generally tend to scratch the itchy area when they experience itching, which can be a contributing factor to the worsening of dermatitis. However, by significantly reducing or eliminating itching in this way, it becomes possible to prevent the dermatitis from becoming severe.

[0168] Furthermore, the effectiveness of the C-ring gel formulation was superior to that of the CNP gel formulation in all cases. In particular, the C-ring gel formulation showed superior immediate and sustained action, and had a stronger antipruritic effect compared to the CNP gel formulation. It was confirmed that these effects could not be obtained with the gel base.

[0169] 3.2 Comparison of C-ring gel formulations and gel bases using the left / right coloring method In subjects suffering from various types of dermatitis, C-ring gel formulations and gel bases were applied to the affected areas, and changes in symptoms before and after application were observed. The effects are summarized in the table below.

[0170] [Table 7]

[0171] 3.3 Confirmation of the efficacy of C-ring gel formulations in psoriasis The therapeutic effects on psoriasis cases are summarized below. Similar to the above, the C-ring gel formulation was applied to the psoriatic lesions, and changes in symptoms before and after application were observed. Where possible, as a comparative example, the same subjects were treated with the CNP gel formulation applied to lesions that had not received the C-ring gel formulation, and changes in symptoms before and after application were observed. The test results, along with the subjects' age, sex, symptoms, and prescriptions, are shown in the table below.

[0172] [Table 8]

[0173] [Table 9]

[0174] [Table 10]

[0175] Figure 1 shows the results after 3 days of application to the lower legs of a patient with psoriasis (P6), where C-rings and CNP gel formulations were applied to the left and right legs separately using the left-right application method. On the right lower leg where C-rings were applied, scaling almost completely disappeared and redness was reduced. However, on the left lower leg where CNP was applied (as a comparison), scaling became less noticeable but persisted, and erythema and infiltration only slightly improved, not showing the same effect as with C-rings.

[0176] The C ring was found to have a more rapid onset of action for psoriasis than conventional topical steroids and vitamin D3 preparations, and compared to biological agents, it required less effort to administer, resulting in improved treatment satisfaction and quality of life (QOL). Furthermore, the C ring showed a significantly greater therapeutic effect than CNP and demonstrated efficacy at lower concentrations. Remarkably, it showed high therapeutic efficacy against thick scales that were not adequately treated with CNP, exhibiting rapid improvement within minutes and subsequent maintenance of remission. Psoriasis is characterized by multiple erythematous lesions with thick scales that appear throughout the body, and the shedding of these scales significantly impairs QOL due to cosmetic problems. However, topical C ring therapy can improve the QOL of psoriasis patients at an early stage. Psoriasis is a chronic inflammatory skin disease that is difficult to treat. Currently, treatment options for psoriasis include topical therapy with topical steroids and vitamin D3 preparations, treatment with ultraviolet irradiation, cyclosporine, etretinate, and, more recently, biological agents used for moderate to severe cases. However, while the efficacy of biological agents is appreciated, concerns have been raised about their high cost, potential side effects from long-term use, and the cumbersome nature of subcutaneous injection. In topical therapy, few cases can achieve remission with vitamin D3 alone, and continued use of steroids is often unavoidable. However, long-term topical steroid use can easily lead to skin atrophy and adrenal insufficiency. Furthermore, with vitamin D3, caution is needed regarding hypercalcemia when used in individuals whose skin has thinned due to long-term topical steroid use or etretinate use, leading to increased absorption of topical medications, or in patients with impaired renal function. In contrast, the C-ring of the present invention, as described above, not only exhibits superior effects compared to conventional treatments but also addresses the aforementioned concerns.

[0177] 4. Confirmation of its effectiveness as a cosmetic product. The effects of cosmetics containing the C ring were evaluated based on their use as gels, bath additives, and hair care products (shampoo, conditioner) or body soaps containing the C ring, and their effects were confirmed. 4.1.1 Confirmation of skin texture improvement effect (comparison between C-ring gel formulation and CNP gel formulation) The subjects were prescribed the C-ring gel formulation and the CNP gel formulation described above. The C-ring gel formulation was applied to the right side of each subject's cheek and around their eyes, and the CNP gel formulation was applied to the left side. Changes in skin condition were observed and compared. The cases and evaluations are summarized in the table below. Changes in skin condition were determined based on the subject's subjective evaluation and objective observation by the inventor, a physician.

[0178] [Table 11]

[0179] [Table 12]

[0180] Furthermore, the following is a summary of examples where the C-ring gel formulation was applied without differentiating between the left and right sides of the face. Changes in skin condition were assessed using the same method as described above.

[0181] [Table 13]

[0182] In summary, the C ring of the present invention has been shown to have a moisturizing effect on the skin and can improve skin texture. Furthermore, it has been shown to be effective in improving skin quality such as whitening, reducing blemishes and dullness, and anti-aging (sagging, firmness, and deep wrinkles), as well as improving mucous membrane conditions such as chapped lips.

[0183] In all subjects, compared with the site where the CNP gel preparation was applied, for the site where the C-ring gel preparation was applied, a remarkable improvement effect on skin texture and its maintenance were observed. Specifically, effects such as the skin becoming smooth, moist, with a refined texture, firm and tightened, soft, suppression of skin dryness, less prominent fine wrinkles, replenishment and maintenance of skin moisture and oil, shallower and less prominent crow's feet, disappearance of skin tingling sensation, relief of itching, relaxation of skin roughness, and maintenance of healthy skin state were significantly observed for the site where the C-ring gel preparation was applied compared with the site where the CNP gel preparation was applied.

[0184] Also, as a result of targeting subjects from their 20s to 60s, regardless of age, effects such as improvement and disappearance of wrinkles, improvement of cheek sagging, and replenishment and maintenance of skin moisture, oil, and moisture were observed. Also, effects such as the skin becoming firm and taut, the cheeks rising, disappearance of skin tingling sensation, and relaxation of skin roughness were observed. These effects were significantly observed for the site where the C-ring gel preparation was applied compared with the CNP gel preparation, and the effect was even greater compared with the CNP gel application site. Furthermore, in subjects in their 40s to 60s, immediately after application of the C-ring gel preparation, effects such as improvement of sagging, wrinkles, and dryness, tightening of the skin, disappearance of dullness, spots, sagging, and dark circles were significantly observed, and the effect was greater than that when the CNP gel preparation was applied.

[0185] In addition, the onset of the effect was significantly faster for the C-ring gel preparation compared with the CNP gel preparation. In most cases, starting around 2 minutes after application of the C-ring gel preparation, effects such as disappearance and less prominence of wrinkles, swelling of the skin, and firmness were confirmed. Also, this effect persisted for at least several hours thereafter. There were no irritating symptoms associated with the application of the C-ring gel preparation.

[0186] 4.1.2 Confirmation of skin texture improvement effect (comparison between C-ring gel preparation and gel base) To examine the presence or absence of the gel-based contribution in the effects of the C-ring gel preparation and the CNP gel preparation, a C-ring gel preparation was applied to the right side of the face of one subject, and a gel base was applied to the left side of the face, and the changes in the skin condition of the subject's face were observed.

[0187]

Table 14

[0188] In the area where the gel base was applied, the dry feeling and the tingling feeling of the skin were not improved. On the other hand, in the area where the C-ring gel preparation was applied, after 2 minutes of application, the skin became soft and moist, and the tingling feeling was improved. Also, the skin texture was improved and the fine wrinkles became less noticeable.

[0189] 4.2 Observation of the state of the mucosa to which the C-ring gel preparation was applied For normal subjects with symptoms of chapped lips, a C-ring gel preparation was applied, the changes in the state of the lip mucosa were observed, and the results were summarized in the following table. The changes in the state of the mucosa were determined based on the subjective evaluation of the subjects and the objective observation by the inventor as a doctor.

[0190]

Table 15

[0191] As described above, it was confirmed that the cyclic peptide of the present invention also has an effect of improving the state of the mucosa and has an immediate effect with respect to the above-described effects.

[0192] 4.3 Observation of the state of the scalp and hair to which the C-ring gel preparation was applied For normal subjects with symptoms of the scalp and hair, a C-ring gel preparation was applied, the changes in the state of the scalp and hair were observed, and the results were summarized in the following table. The changes in the state of the hair and scalp were determined based on the subjective evaluation of the subjects and the objective observation by the inventor as a doctor.

[0193]

Table 16

[0194] In summary, the C-ring of the present invention can moisturize and retain moisture in the scalp and hair, replenish and maintain appropriate moisture and oil levels, improve and prevent dryness, improve seborrhea, and cleanse the scalp and hair. Furthermore, it has been shown to be effective in suppressing scalp itchiness and dandruff, as well as in preventing thinning hair and hair loss, promoting hair growth, preventing and preventing hair loss, stimulating hair growth, and improving hair loss and hair nourishment after illness or childbirth.

[0195] 4.4 Observation of skin condition when using bath additives containing a C ring Subjects were bathed once a day for 14 days in 37-41°C water (100 ml of a 20 μM C ​​ring solution dissolved in 200 L of water) with a C ring dissolved to a concentration of 0.01 μM. The subjects' skin condition was compared to when they were bathed in plain water (water only). The cases and evaluations are summarized in the table below. Changes in skin condition were determined based on the subjects' subjective evaluations and objective observations by the inventor, a physician.

[0196] [Table 17]

[0197] In summary, the bath additive containing the C ring of the present invention not only alleviates heat rash, cracked and chapped skin, but also shows improvement in eczema. Furthermore, it was found to improve skin dryness and itchiness, demonstrating its effectiveness in improving skin condition.

[0198] 4.5 Observation of scalp and hair condition or skin condition when using hair cosmetics (shampoo, conditioner) or body soap containing a C ring.

[0199] 4.5.1 A shampoo containing a C ring was formulated and manufactured with the following composition. [Table 18] After heating and dissolving A and B at 70°C, B was added to A, followed by stirring and mixing. Further, C was added at 40 - 35°C while stirring, and the mixture was cooled to room temperature while stirring.

[0200] 4.5.2 The treatment containing the C ring was formulated and manufactured with the following composition.

Table 19

[0201] 4.5.3 The body soap containing the C ring was formulated and manufactured with the following composition.

Table 20

[0202] The shampoo, rinse or body soap manufactured according to the above was used once a day for 14 days, and the results in the scalp and hair condition or skin condition of the subjects were evaluated. Also, the cases and evaluations were summarized in the following table. Regarding the changes in skin condition, dandruff, erythema, etc. on the scalp were evaluated visually by the subjects, and itching, moist feeling, hair combability, gloss, stiffness of the scalp and hair were evaluated as the subjective evaluations of the subjects.

[0203]

Table 21

[0204] In summary, the use of the hair product containing the C ring of the present invention showed immediate improvement in scalp itchiness, erythema, and dryness. Furthermore, it was shown to be effective in improving thinning hair and hair loss when used continuously for two weeks or more. In addition, the use of the body soap containing the C ring of the present invention was shown to have an improving effect on dry and sensitive skin.

[0205] 5. Confirmation of the effectiveness of alopecia treatment. The effects of C-ring gel formulations and CNP gel formulations on various hair loss symptoms were observed. The cases and evaluations are summarized in the table below. Changes in symptoms were determined based on the subjective evaluations of the subjects and objective observations by the inventor, a physician.

[0206] [Table 22]

[0207] [Table 23]

[0208] 5.1 Confirmation of the effectiveness of AGA treatment The effects of C-ring gel formulations and CNP gel formulations on the symptoms of AGA were observed after application. The cases and evaluations are summarized in the table below. Changes in symptoms were determined based on the subjective evaluations of the subjects and objective observations by the inventor, a physician.

[0209] [Table 24]

[0210] Figure 2 shows the results before and after application of a C-ring gel formulation to a patient (A11) with male pattern baldness (M-type and O-type). After 7 weeks of application, hair became stronger, thicker, and hair loss dramatically decreased. As a result, hair density increased, and thinning hair became less noticeable. These phenomena were more pronounced with the C-ring gel formulation than with CNP. In particular, in patients with M-type baldness whose hairlines had receded, the hairlines advanced, and the hair growth, thickening, and hair restoration effects on M-type baldness were much more pronounced than with CNP.

[0211] 5.2 Case Summary In the cases of subjects with female pattern baldness, male pattern baldness, alopecia universalis, serpentine alopecia, and alopecia multiplex described above, when the C-ring gel formulation according to the example was applied, hair loss was significantly reduced, the area of ​​terminal hair growth expanded, and its growth was accelerated. Furthermore, existing hair gained firmness and increased its elasticity. In all cases, the improvement in symptoms was significantly more pronounced compared to when the CNP gel formulation according to the comparative example was applied. In other words, the C-ring gel formulation was more effective than the CNP gel formulation for the above-mentioned symptoms. Furthermore, the C-ring gel formulation improved seborrheic dermatitis, cleansed the scalp, and suppressed dandruff. It also prevented graying hair, promoted the growth of black hair, and improved thinning hair. Moreover, its itchiness-relieving effect was achieved within 10 minutes, demonstrating its high immediate efficacy.

[0212] 6. Confirmation of the effectiveness of the treatment for rhinitis. 6.1 Case The effects of C-ring nasal spray and CNP gel nasal spray on rhinitis and other symptoms in subjects were observed. The cases and evaluations are summarized in the table below. Changes in symptoms were determined based on the subjects' subjective evaluations and objective observations by the inventor, a physician.

[0213] [Table 25]

[0214] [Table 26]

[0215] 6.2 Case Summary In all of the above cases, when the C-ring nasal spray described in the examples was applied, both rhinorrhea and nasal congestion improved and resolved more rapidly compared to when the CNP nasal spray described in the comparative examples was applied. In other words, the C-ring nasal spray had superior immediate effect compared to the CNP nasal spray. Furthermore, the efficacy of the C-ring nasal spray was equivalent to or better than that of the CNP nasal spray, and its effect lasted longer, suppressing the recurrence of symptoms.

[0216] 7. Analysis of the binding state of human CNP to type B receptors As explained above with data based on various clinical cases, the C-ring compound of the present invention exhibits superior pharmacological effects against various diseases compared to conventional CNPs. For reference, the following experimental report explains that these pharmacological effects are also supported by the results of the three-dimensional structural analysis of the compound conducted by the inventors. To investigate the binding state between human CNP (CNP-22) and its receptor, the type B receptor (NPR-B), in silico analysis was performed using homology modeling based on three-dimensional structures. Swiss-Pdb viewer and SWISS-MODEL were used for modeling.

[0217] 7.1 Template Structure First, prior to the above analysis, a template structure was selected to examine the binding state between human CNP and the type B receptor. The three-dimensional structure of the rat NPR-A complex with rat ANP peptide (PDB ID: 1T34) was used as this template structure. Rat NPR-A is a homodimer consisting of A and B chains. The three-dimensional structure of this rat NPR-A was determined by X-ray crystallography with 21 residues from Cys7 to Arg27 of rat ANP bound to it. The three-dimensional structure of rat NPR-A was obtained from the Protein Data Bank, a protein structure database. Furthermore, the amino acid agreement between human NPR-B and rat NPR-A is 45%.

[0218] In this specification, the numbers accompanying amino acid residue symbols indicate the order of that amino acid residue from the N-terminus within the peptide. Therefore, for example, in human CNP, the notation "Cys6" refers to the sixth cysteine ​​from the N-terminus of the human CNP amino acid sequence. The notation for amino acid residues at other positions is the same.

[0219] 7.2 CNP Peptide Model In this study, we used Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys (SEQ ID NO: 5), which is the amino acid sequence of the Cys6-Cys22 region of human CNP (CNP-22), as the peptide model for CNP. Naturally, the region of this CNP peptide model coincides with the C ring of the present invention.

[0220] 7.3 Homology Modeling To infer the amino acid residues involved in the binding of human CNP to human NPR-B, a complex model of the CNP peptide bound to human NPR-B was constructed using homology modeling. Specifically, a human CNP peptide model was created based on the template structure of rat ANP peptide, and a model structure of human NPR-B was created based on the template structure of rat NPR-A using homology modeling. Next, we inferred the amino acid residues directly involved in the interaction from the amino acid residues detected between the human CNP peptide model and human NPR-B.

[0221] These results showed that the CNP peptide model is bound to the human NPR-B dimer, sandwiched between its A and B chains. In the constructed complex model, hydrophobic bonds were inferred between the CNP peptide model and the A chain of NPR-B via the side chains of Phe2 and Leu4, and hydrogen bonds were inferred between the main chain of Cys1 and the side chains of Lys5 and Arg8. Furthermore, hydrophobic bonds were inferred between the CNP peptide model and the B chain of NPR-B via the side chain of Met12, and hydrogen bonds were inferred between the main chain of Gly16 and the side chain of Arg8. Note that Cys1, Phe2, Leu4, Lys5, Arg8, Met12, and Gly16 in the CNP peptide model correspond to Cys6, Phe7, Leu9, Lys10, Arg13, Met17, and Gly21 in human CNP (CNP-22), respectively. These amino acid residues in human CNP are thought to be residues that contribute to the activation of NPR-B.

[0222] 7.4 Discussion Based on the above, structural analysis using in silico analysis suggests that the residues contributing to NPR-B activation in human CNP are located in its cyclic portion, i.e., the C ring.

[0223] Furthermore, NMR analysis has revealed that ANP does not adopt a specific three-dimensional structure in aqueous solution but fluctuates considerably, and the same is thought to be true for CNP. In this regard, if the amino acid residues in the cyclic portion of human CNP contribute to binding to human NPR-B, then it was hypothesized that the amino acid residues in the tail portion, due to their large fluctuations, would make it difficult for human CNP to enter the narrow CNP binding site sandwiched between the A and B chains of human NPR-B. Therefore, unlike human CNP, the cyclic portion of human CNP is a smaller molecule compared to CNP, and is thought to be able to enter the CNP binding site of NPR-B more easily and rapidly.

[0224] In other words, it is presumed that the cyclic portion of human CNP has a higher affinity for human NPR-B than CNP. Therefore, although the molecular biological mechanism by which the cyclic peptide of the present invention has superior pharmacological efficacy compared to CNP is not necessarily clear, the results of in silico analysis suggest that the CNP cyclic structure contributes to the activation of NPR-B and can bind more easily and rapidly than CNP. This supports the aforementioned clinical cases in which the C-ring compound of the present invention exhibits superior pharmacological effects against various diseases compared to conventional CNP.

[0225] Furthermore, even C-rings derived from other species with amino acid sequences similar to those of humans are presumed to have the same effect as human-derived C-rings because they possess a similar structure.

[0226] 8. Estimation of substituteable amino acid residues in the CNP cyclic region Using the model structure of the constructed complex, we investigated the possibility of substituting amino acid residues other than those inferred to be involved in the interactions. Specifically, to investigate whether substituted peptides can bind to NPR-B when amino acid residues other than those suspected to interact are substituted with other amino acids, we created mutant models of CNP and analyzed the interactions. Swiss-Pdb viewer was used for modeling.

[0227] Specifically, we investigated whether the amino acid residues Gly8, Leu11, Asp12, Ile14, Gly15, Ser16, Ser18, Gly19, and Leu20 of human CNPs can be substituted with other amino acids, based on the following points. • It does not cause steric hindrance when binding to NPR-B. No interatomic collisions are observed in the NPR-B and CNP mutant model structures. • Does not affect the electrostatic potential of the surface. • The intramolecular energy value does not increase significantly (no unnatural angles or twists occur in the bonds between atoms). • It does not form hydrogen bonds between the NPR-B chain and CNP, or within the CNP chain, which are not normally observed. • Does not create cavities or gaps.

[0228] Of the values ​​mentioned above, the intramolecular energy was calculated using the Compute Energy command in Swiss-Pdb viewer. The intramolecular energy was calculated in kilojoules / mol (KJ / mol) based on the sum of the bond length, bond angle, torsion, and bond energy between atoms.

[0229] Analysis revealed that Gly8, Leu11, Ile14, Ser16, Ser18, and Leu20 are substitutable amino acid residues. The results are summarized in the table below. [Table 27]

[0230] From the above, it is suggested that even if the amino acid residues corresponding to the substitutions listed in the table above are substituted in the cyclic portion of human CNP, i.e., the peptide represented by formula II, the peptide with such substitutions will exhibit the same effect as the peptide consisting of the amino acid sequence represented by formula II.

[0231] 8. Confirmation of the therapeutic effect of cyclic peptides with substituted amino acids. Next, cyclic peptides with some amino acid substitutions were subjected to the following tests to confirm their effects. The method for producing the above cyclic peptides and the method for confirming the amino acid sequence of the produced peptides were the same as the method for producing the cyclic peptides and the mass spectrometry method described above. The cyclic peptide variants used in the tests were those listed in the table below. The table below is an example of the cyclic peptides of the present invention and is not limited to these. In the table below, for example, "0-2" indicates that any 0, 1, or 2 amino acids in the sequence may be mutated. In the cases of SEQ ID NOs. 22-31, 42-47, 54-56, and 60-62, the case of SEQ ID NO. 3 (i.e., 0 amino acid mutations) can be excluded in all cases.

[0232] [Table 28-1]

[0233] [Table 28-2]

[0234] 8.1 Confirmation of effects on the skin The obtained cyclic peptide was mixed with purified water at concentrations of 1, 5, 30, 100, and 500 μg / ml and applied to the affected area. In the table, formulations A to E refer to cyclic peptide concentrations of 1, 5, 30, 100, and 500 μg / ml, respectively. Furthermore, treatment with purified water without the peptide showed no effect, confirming that it was not a placebo effect.

[0235] [Table 29-1]

[0236] [Table 29-2]

[0237] Table 29-3

[0238] Table 29-4

[0239] Table 29-5

[0240] Table 29-6

[0241] Table 29-7

[0242] Table 29-8

[0243] Table 29-9

[0244] Table 29-10

[0245] Table 29-11

[0246] Table 29-12

[0247] Table 29-13

[0248] [Table 29-14]

[0249] [Table 29-15]

[0250] [Table 29-16]

[0251] [Table 29-17]

[0252] [Table 29-18]

[0253] The above results demonstrate that even cyclic peptides in which some amino acids of the cyclic peptide of the present invention are substituted can exhibit effects equivalent to or better than those of the cyclic peptide represented by formula II (SEQ ID NO: 3). Furthermore, even when the substituted cyclic peptides were mixed and applied, similar effects could be obtained by applying an effective amount of the cyclic peptide.

[0254] In particular, subjects with atopic dermatitis, eczema, etc., showed immediate effects immediately after a single application of 1 μg / ml to 500 μg / ml to the affected area, including the disappearance of itching, epithelialization of erythema, infiltration, papules, and scratches, cessation of exudate, and epithelialization of cracks. Furthermore, the effects lasted for more than a week after just one application. When applied to healthy skin or rough skin, it exhibited moisturizing effects within minutes of application, improving dryness, providing and maintaining appropriate elasticity and flexibility to the skin and mucous membranes, making the skin softer, firmer, and tighter. In addition, fine wrinkles and sagging were improved in the applied area, and dullness and blemishes became less noticeable. Furthermore, it has the effect of preventing photosensitivity and photodermatitis, and preventing or reducing the occurrence of inflammatory symptoms caused by light. These effects lasted for more than a week after just one application.

[0255] In particular, in the test examples S119-S129, which were conducted using the left-right smear method (tests on the same person, with one side treated with a CNP cyclic peptide and the other side with a cyclic peptide with 4 amino acid substitutions (e.g., SEQ ID NO: 58)), it was confirmed that cyclic peptides such as SEQ ID NO: 58, even at a low concentration of only 1 μg / ml, were effective in suppressing inflammatory symptoms, i.e., itching, erythema, scaling, and infiltration, within minutes of application to atopic dermatitis, psoriasis, and eczema, as well as promoting the drying and epithelialization of scratches. The effect was long-lasting, and itching did not occur even after discontinuation of application. In psoriasis, within minutes of applying the amino acid-substituted CNP cyclic peptide, hard plaques mainly consisting of well-defined erythema and scaling became smooth, soft, and flat, and the boundary with normal skin began to become indistinct. After 7-8 minutes, the erythema and scaling further improved, the skin color became almost normal, and the scaling became almost invisible, resulting in flattening. Furthermore, the effects were long-lasting, and the smooth, improved condition with reduced scaling and erythema did not recur even after 3 weeks without application.

[0256] Furthermore, the efficacy of applying 1 μM of CNP cyclic peptide is equivalent to or better than that of CNP at concentrations of 10 μM to 50 μM. In addition, the newly developed CNP cyclic peptide with some amino acid substitutions not only has a higher therapeutic effect compared to CNP and the CNP cyclic peptide without amino acid substitutions, but also exhibits rapid action and is effective at very low concentrations.

[0257] 8.2 Confirmation of effects on the scalp or hair The obtained cyclic peptide was mixed with purified water at concentrations of 1, 5, 30, 100, and 500 μg / ml and applied to the affected area. In the table, formulations A to E refer to cyclic peptide concentrations of 1, 5, 30, 100, and 500 μg / ml, respectively. Furthermore, treatment with purified water without the peptide showed no effect, confirming that it was not a placebo effect.

[0258] [Table 30-1]

[0259] [Table 30-2]

[0260] [Table 30-3]

[0261] [Table 30-4]

[0262] [Table 30-5]

[0263] [Table 30-6]

[0264] [Table 30-7]

[0265] [Table 30-8]

[0266] [Table 30-9]

[0267] [Table 30-10]

[0268] [Table 30-11]

[0269] [Table 30-12]

[0270] [Table 30-13]

[0271] The above results demonstrate that even cyclic peptides in which some amino acids of the cyclic peptide of the present invention are substituted can exhibit effects equivalent to or better than those of the cyclic peptide represented by formula II (SEQ ID NO: 3). Furthermore, even when the substituted cyclic peptides were mixed and applied, similar effects could be obtained by applying an effective amount of the cyclic peptide.

[0272] In particular, in the U87-U88 test examples, which were conducted using the left-right smear method (tests on the same person using a CNP cyclic peptide on one side and a cyclic peptide with 4 amino acid substitutions (e.g., SEQ ID NO: 58) on the other side), it was confirmed that cyclic peptides such as SEQ ID NO: 58, even at a low concentration of only 1 μg / ml, have an effect in suppressing itching and other symptoms in atopic dermatitis, psoriasis, and eczema within minutes of starting use.

[0273] Furthermore, the efficacy of applying 1 μM of CNP cyclic peptide was equivalent to or better than that of CNP at concentrations of 10 μM to 50 μM. Compared to CNP and CNP cyclic peptide without amino acid substitution, it not only showed higher therapeutic efficacy but also demonstrated rapid action and effectiveness at very low concentrations.

[0274] In particular, when applied to areas of hair loss or hair growth, it prevented hair loss in the applied area, promoted hair growth, gave hair firmness and body, increased hair volume, and dramatically reduced hair loss. It also showed effects such as hair nourishment, hair growth promotion, and improvement / prevention of thinning hair. In particular, the hair that grew tended to be coarse and not gray. Furthermore, these effects were not observed with conventional alopecia treatments such as CNP. Specifically, even in cases of refractory multiple alopecia or serpentine alopecia, hair growth was observed remarkably quickly after just one application, with results confirmed the next day. This effect persisted even after discontinuation of application. In addition, in individuals with AGA and healthy individuals, immediate effects were observed from the day after application, giving hair firmness and body, increasing hair volume, and dramatically reducing hair loss. This effect persisted even after discontinuation of application. Furthermore, in addition to the effects mentioned above, improvements and preventative effects were observed in scalp dermatitis and other skin conditions.

[0275] Therefore, it can improve or prevent skin inflammation associated with alopecia. This effect is particularly useful when alopecia is exacerbated by the condition of the skin at the application site, such as the scalp. Furthermore, when used as a topical agent, as described above, it exhibits moisturizing and skin-conditioning effects at the application site. In other words, it can remove dandruff and itchiness, suppress their occurrence, moisturize the hair and scalp, improve and prevent dryness, improve seborrheic dermatitis, and keep the scalp and hair healthy.

[0276] 8.3 Confirmation of effects on the nose The obtained cyclic peptide was mixed with purified water at concentrations of 1, 5, 30, 100, and 500 μg / ml and applied to the affected area. In the table, formulations A to E refer to cyclic peptide concentrations of 1, 5, 30, 100, and 500 μg / ml, respectively. Furthermore, treatment with purified water without the peptide showed no effect, confirming that it was not a placebo effect.

[0277] [Table 31-1]

[0278] [Table 31-2]

[0279] [Table 31-3]

[0280] [Table 31-4]

[0281] [Table 31-5]

[0282] [Table 31-6]

[0283] [Table 31-7]

[0284] [Table 31-8]

[0285] The above results demonstrate that even cyclic peptides in which some amino acids of the cyclic peptide of the present invention are substituted can exhibit effects equivalent to or better than those of the cyclic peptide represented by formula II (SEQ ID NO: 3). Furthermore, even when the substituted cyclic peptides were mixed and applied, similar effects could be obtained by applying an effective amount of the cyclic peptide.

[0286] A single nasal application of 0.1 ml at concentrations ranging from 1 μg / ml to 500 μg / ml to the affected area in each nostril immediately stopped nasal discharge, improved nasal congestion, and quenched itching and sneezing of the nasal mucosa. Furthermore, a single application provided sustained effects that lasted for a full day, and in some cases, for over a week. Compared to CNP administration, it demonstrated not only higher therapeutic efficacy but also faster onset and the ability to act at very low concentrations.

[0287] In particular, in the test examples T41-T44, which were conducted using the left-right smear method (tests on the same person using a CNP cyclic peptide on one side and a cyclic peptide with 4 amino acid substitutions (e.g., SEQ ID NO: 58) on the other side), it was confirmed that cyclic peptides such as SEQ ID NO: 58, even at a low concentration of only 1 μg / ml, have the effect of suppressing erythema, scaling, papules, edema, and itching in atopic dermatitis, psoriasis, eczema, and contact dermatitis within minutes of starting use.

[0288] Furthermore, the efficacy of applying 1 μM of CNP cyclic peptide was equivalent to or better than that of CNP at concentrations of 10 μM to 50 μM. Compared to CNP and CNP cyclic peptide without amino acid substitution, it not only had a higher therapeutic effect but also a rapid onset of action and was found to be effective at very low concentrations. Moreover, the newly developed CNP cyclic peptide with some amino acid substitution showed efficacy even at even lower concentrations where the non-substituted CNP cyclic peptide was ineffective. This effect was rapid, resulting in significant improvement of nasal discharge and congestion, as well as stopping mucosal itching and sneezing. This invention allows for safe use even in subjects who experience strong local irritation from conventional rhinitis treatments such as steroid drugs and do not wish to use nasal sprays, as it causes absolutely no local irritation.

Claims

1. A composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof, Cyclic peptides are Formula II: 【Chemistry 1】 (Sequence No. 3) In the formula, the line connecting the two Cys represents a disulfide bond. It consists of an amino acid sequence represented by, or an amino acid sequence in which one or two amino acids are deleted, substituted, or added in the amino acid sequence of SEQ ID NO: 3, and has CNP activity. It contains at least one constituent material selected from the group consisting of thickening and gelling agents, oily components, alcohols, fatty acids, organic acids, UV absorbers, UV scattering agents, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active components, solvents, antioxidants, chelating agents, fragrances, preservatives, and animal and plant extracts. Methods for treating and / or preventing dermatitis, methods for reducing or eliminating itching, methods for treating erosions and ulcers, or skincare methods. Methods for the treatment and / or prevention of dermatitis selected from the group consisting of eczema, atopic dermatitis, contact dermatitis, photosensitivity, psoriasis, acne, cystic acne, seborrheic dermatitis, and itching. Methods for improving and preventing rough skin, sensitive skin, dry skin, oily skin, photosensitivity, wrinkles, sagging, dullness, dandruff, and itchiness. Treatment and / or prevention methods for thinning hair, alopecia, and / or methods for promoting hair growth and / or hair nourishment, methods for preventing and / or preventing hair loss, Methods for preventing dandruff and itching, and / or methods for improving and preventing dryness of the hair and scalp, and / or methods for preventing and improving seborrheic dermatitis of the scalp, or For use in the treatment and / or prevention of rhinitis and sinusitis, The aforementioned composition.

2. A composition comprising a cyclic peptide or a pharmaceutically acceptable salt thereof, Cyclic peptides are Formula I: 【Chemistry 2】 During the ceremony, X １ This indicates Gly or Ala, X ２ This indicates Leu, Ala, or Met. X ３ This indicates Ile or Val, X ４ This represents Ser, Thr, Ala, Val, Ile, or Leu. X ５ This indicates Ser, Thr, or Ala. X ６ This represents Leu, Ala, Val, Ile, Met, or Phe. The line connecting the two Cys represents a disulfide bond. An amino acid sequence represented by , consisting of an amino acid sequence selected from SEQ ID NOs. 6-21, 32-41, 48-53, 57-59, or an amino acid sequence in which one or two amino acids are deleted, substituted, or added in the amino acid sequences of SEQ ID NOs. 6-21, 32-41, 48-53, 57-59, and having CNP activity. The amino acid sequence does not have peptide bonds other than those between the amino acids that make up the amino acid sequence. It contains at least one constituent material selected from the group consisting of thickening and gelling agents, oily components, alcohols, fatty acids, organic acids, UV absorbers, UV scattering agents, powders, pigments, surfactants, polyhydric alcohols / sugars, polymers, physiologically active components, solvents, antioxidants, chelating agents, fragrances, preservatives, and animal and plant extracts. Methods for treating and / or preventing dermatitis, methods for reducing or eliminating itching, methods for treating erosions and ulcers, or skincare methods. Methods for the treatment and / or prevention of dermatitis selected from the group consisting of eczema, atopic dermatitis, contact dermatitis, photosensitivity, psoriasis, acne, cystic acne, seborrheic dermatitis, and itching. Methods for improving and preventing rough skin, sensitive skin, dry skin, oily skin, photosensitivity, wrinkles, sagging, dullness, dandruff, and itchiness. Treatment and / or prevention methods for thinning hair, alopecia, and / or methods for promoting hair growth and / or hair nourishment, methods for preventing and / or preventing hair loss, Methods for preventing dandruff and itching, and / or methods for improving and preventing dryness of the hair and scalp, and / or methods for preventing and improving seborrheic dermatitis of the scalp, or For use in the treatment and / or prevention of rhinitis and sinusitis, The aforementioned composition.

3. The composition according to any one of claims 1 to 2, wherein the cyclic peptide is substituted with a substituent that can be substituted for a hydrogen atom, hydroxyl group, carboxyl group, amino group, or imino group.

4. A composition according to any one of claims 1 to 3, which is an external preparation.

5. The composition according to any one of claims 1 to 4, wherein the dosage form is a solid, semi-solid, powder, liquid, spray, ointment, cream, emulsion, gel, or patch.

6. A composition according to any one of claims 1 to 5, comprising a cyclic peptide or a pharmaceutically acceptable salt thereof at a concentration of 0.0001 to 1,000,000 μg / mL.

7. A composition according to any one of claims 1 to 6, to be used as a pharmaceutical, quasi-drug, or cosmetic.

8. A composition according to any one of claims 1 to 7, for application to the target skin and / or mucous membrane.

9. The composition according to claim 8, wherein the mucous membrane is the lips, oral cavity, nasal cavity, eye, or vagina.

10. Use of the composition according to any one of claims 1 to 9 for the manufacture of a pharmaceutical product.

11. A pharmaceutical product comprising the composition described in any one of claims 1 to 9.

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