WO2017022728A1 - Cnp環状ペプチド並びに該環状ペプチドを含む医薬品、外用剤および化粧料 - Google Patents
Cnp環状ペプチド並びに該環状ペプチドを含む医薬品、外用剤および化粧料 Download PDFInfo
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- WO2017022728A1 WO2017022728A1 PCT/JP2016/072562 JP2016072562W WO2017022728A1 WO 2017022728 A1 WO2017022728 A1 WO 2017022728A1 JP 2016072562 W JP2016072562 W JP 2016072562W WO 2017022728 A1 WO2017022728 A1 WO 2017022728A1
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- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
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- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
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- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
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- C07K14/575—Hormones
- C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
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Definitions
- the present invention relates to a CNP cyclic peptide and pharmaceuticals, external preparations and cosmetics containing the cyclic peptide.
- CNP C-type natriuretic peptide
- ANP and BNP which are classified into the same family. It has been known.
- natriuretic use and blood pressure lowering action are weaker than ANP and BNP, but it is known to have a strong effect of increasing intracellular cyclic guanosine monophosphate (cGMP) in vascular smooth muscle cells and the like.
- cGMP cyclic guanosine monophosphate
- CNP is known to have highly conserved amino acids in individual species, there is almost no difference between them, and the structure is known to have a cyclic part and a tail part as a common structure.
- CNP the minimally active structure for increasing cGMP in vascular smooth muscle cells
- C ring a cyclic part of CNP
- Patent Documents 1 and 6 Recently, several therapeutic agents and treatment methods using such CNP have been known (Patent Documents 1 to 5), and it has been reported that CNP cyclic peptides are effective for arthritis ( Patent Document 6).
- Patent Documents 2 to 4 various agents are used in alopecia, but none of them can exert an effect that is more than expected, but in a therapeutic agent for alopecia including CNP, significant hair growth and hair growth are achieved. It has been proven to be effective (Patent Documents 2 to 4).
- CNP and CNP cyclic peptides are considered to be useful substances for the treatment of various diseases such as arthritis.
- development of substances with higher drug efficacy and efficacy, and substances with even greater immediate effects and sustainability is required.
- dermatitis is accompanied by symptoms such as itching, erythema, and hot flashes in the affected area, and diseases in which erythema with thick scales is seen throughout the body, such as psoriasis, the scales peel off along with the appearance problems, and QOL is significantly impaired.
- QOL social and satisfaction
- rhinitis often involves nasal congestion and rhinorrhea, and if these symptoms can be quickly suppressed, the number of vaginal nose is reduced, resulting in a decrease in patient discomfort.
- a hair thinning agent alopecia treatment agent, a hair growth agent, and a hair growth agent
- an object of the present invention is to provide a novel substance, a novel peptide having a higher medicinal effect and efficacy than conventional ones, a pharmaceutical or an external preparation containing the peptide, particularly a preventive or therapeutic agent or hair growth agent for dermatitis, rhinitis, and alopecia To provide hair restorers, antipruritics, cosmetics, skin care products and the like.
- cyclic CNP is the minimum active structure of cGMP in smooth muscle cells, but the physical property value of the cyclic CNP is not clear.
- therapeutic drugs in which various modifications are added to CNP, but the present inventor deliberately focuses only on the ring part of CNP that is not necessarily high in activity value, and is obtained by deleting the tail part.
- CNP cyclic peptides we have created new substances based on CNP cyclics, such as efficacy, high efficacy, rapid onset of effects, and long-lasting effects.
- the present invention has been completed. That is, the present invention relates to the following.
- [2] The cyclic peptide according to [1] or a derivative thereof, or a pharmaceutically acceptable salt thereof, selected from SEQ ID NOs: 60 to 62.
- [3] The cyclic peptide or derivative thereof according to [1], selected from SEQ ID NOs: 22-31, 42-47 and 54-56, or a pharmaceutically acceptable salt thereof.
- [4] The cyclic peptide or derivative thereof according to [1], or a pharmaceutically acceptable salt thereof, selected from SEQ ID NOs: 6-21, 32-41, 48-53 and 57-59.
- [6] A function equivalent to that of the cyclic peptide represented by the above formulas, which is formed by deleting one or more and six or less of the amino acids in the cyclic peptide of [4], or substituting or adding with another amino acid A cyclic peptide or derivative thereof, or a pharmaceutically acceptable salt thereof.
- [7] [1] An external preparation comprising at least one cyclic peptide and / or derivative thereof and / or pharmaceutically acceptable salt thereof according to any one of [6].
- the external preparation according to [7] which is a dermatitis therapeutic agent, dermatitis preventive agent, antipruritic agent, anti-inflammatory agent, epidermal regeneration promoter or skin care product material.
- the external preparation according to [8] which is a bath preparation, body cleanser, hair cleanser, rinse treatment, tonic, hair oil, hair lotion, and scalp care agent.
- the topical preparation according to [7] which is a therapeutic agent for alopecia, an alopecia preventive agent, a hair restorer and / or a hair growth agent and / or a hair loss preventing agent / preventive agent, and a hair loss preventing cosmetic.
- the external preparation according to [7] which is a scalp care agent for preventing / ameliorating dandruff and itching and / or for improving / preventing drying of hair and scalp and / or improving / preventing seborrhea of scalp.
- the external preparation according to [7] which is a rhinitis therapeutic agent and / or a rhinitis preventive agent and / or a sinusitis therapeutic agent and / or a sinusitis preventive agent.
- [18] The method for using an external preparation according to [18], which is a method for preventing / preventing dandruff and itching and / or a method for improving / preventing drying of hair and scalp and / or a method for preventing / ameliorating seborrhea of the scalp .
- a medicament comprising at least one cyclic peptide or derivative thereof according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof.
- [28] Hypertension, unstable angina, acute myocardial infarction, edematous disease, renal failure, heart failure, immune disease, autoimmune disease, allergic disease, cancer, digestive system disease, Crohn's disease, ulcerative colitis, obesity, metabolic
- a novel cyclic peptide and a composition containing the same can be provided.
- Such a composition is applied to an external preparation for the prevention or treatment of dermatitis, rhinitis, alopecia, as well as a hair growth agent, a hair growth agent, a hair loss prevention agent, an antipruritic agent, etc., all of which are pharmaceuticals, quasi drugs, Provided as skin care products and cosmetics.
- the external preparation of the present invention is more effective than steroid external preparations and CNP in general in terms of effectiveness against dermatitis, and has an immediate effect superior to those preparations / substances in which symptoms generally begin to improve within 3 minutes. Have a greater effect, longer lasting and longer remission.
- the external preparation of the present invention when applied on the skin or mucous membrane of a subject suffering from dermatitis, itching or pain caused by dermatitis, pain (pain), heat, tension, infiltration, erythema
- the symptoms of objective dermatitis can be improved while rapidly relieving or eliminating various perceptible symptoms and conditions such as the above.
- the external preparation of the present invention exerts a moisturizing effect at the application site, and when the stratum corneum is present at the application site, it exerts the effect of adjusting the texture of the application site, and the texture is smooth, dry skin and rough skin Improved, soft skin, moist, wrinkle shallow and inconspicuous, prevent photosensitivity, prevent and improve wrinkles and sagging, prevent and improve dullness and darkness, and even rough lips The effect of improving can be exhibited.
- the external preparation of the present invention when applied to the scalp, has effects of preventing hair loss at the application site and promoting hair growth or hair growth, preventing hair loss and thickening hair.
- the hair that grows tends to be hard and tends to be non-white hair.
- these effects are expressed at an early stage as compared with other active ingredients conventionally used in therapeutic agents for alopecia, such as CNP, and the obtained effects are also large.
- the effect of thickening hair, growing hair quickly, and improving thinning hair is also remarkable.
- the external preparation of the present invention has an immediate effect on rhinitis, has a large effect, is durable, and has a long remission period.
- the cyclic peptide of the present invention is a peptide having a common part in its structure with CNP, which is a hormone originally provided in the body, it is considered that there is less concern about side effects, and no side effects have been discovered or reported so far. .
- the amount of CNP ring having a large molecular weight (> 500D) that is not hydrophobic and absorbed by the body is considered to be very small. That is, it is presumed that the effect on systemic side effects and hemodynamics is minor as long as the amount is appropriate or when applied externally to the skin.
- the external preparation of the present invention is less irritating when applied externally, it can be applied to a face or neck which is a particularly sensitive part for a person with sensitive skin. It can also be applied to pregnant women and breastfeeding people.
- cyclic peptides are used as components of external preparations such as dermatitis treatment / prevention agent, rhinitis treatment / prevention agent, alopecia treatment / prevention agent, hair growth agent, hair growth agent, hair loss treatment / prevention agent, and antipruritic agent. Can also be used. Furthermore, it can be used as a material for skin care products, quasi drugs, and cosmetics.
- medicines utilizing the above CNP activity such as hypertension, unstable angina, acute myocardial infarction, edematous disease, renal failure, heart failure, immune disease, autoimmune disease, allergic disease, cancer, digestive system
- the above cyclic peptides as an alternative to CNP in medicines for the treatment of diseases, obesity and metabolic syndrome.
- the cyclic peptide is a peptide smaller than CNP, the production cost is a fixed price, and a preparation using this can be provided at a lower cost than CNP.
- CNP cyclic peptide referred to in this specification (hereinafter sometimes referred to as “CNP cyclic peptide”, “C ring” or “C ring compound”) is derived from wild-type CNP as described above.
- the wild-type CNP includes not only those derived from humans but also species having the same sequence as human wild-type CNP, such as, but not limited to, those derived from monkeys, pigs, birds and rats.
- the C-ring peptide is not limited to that derived from humans, but includes, but not limited to, those derived from monkeys, pigs, birds, rats, etc., and it goes without saying that the effects of the present invention can be substituted as a matter of course.
- the cyclic peptide of the present invention includes those obtained by mutating the cyclic peptide. That is, the mutant of the present invention can be obtained by deleting an amino acid in a cyclic peptide, or substituting or adding it with another amino acid as long as it has CNP activity.
- Formula I (SEQ ID NO: 1) Where X 1 represents Gly or Ala; X 2 represents Leu, Ala or Met; X 3 represents Ile or Val, X 4 represents Ser, Thr, Ala, Val, Ile or Leu, X 5 represents Ser, Thr or Ala, X 6 represents Leu, Ala, Val, Ile, Met or Phe;
- the line connecting the two Cys represents a disulfide bond, Having an amino acid sequence represented by The amino acid sequence is a cyclic peptide having no peptide bond other than the amino acids constituting the amino acid sequence.
- the present invention is a cyclic peptide having the CNP activity, the amino acid sequence of SEQ ID NO: 1, wherein the amino acid sequence does not have a peptide bond other than the amino acids constituting the amino acid sequence It is.
- the amino acid sequence of SEQ ID NO: 3 can be excluded from the amino acid sequence of SEQ ID NO: 1.
- Such a cyclic peptide like CNP, binds to a receptor NPR-B (also known as GC-B) having a guanylate cyclase domain and promotes the production of cGMP. It is presumed to have actions such as renin / aldosterone secretion suppression, sympathetic nerve suppression, and hypertrophy suppression.
- Another aspect of the present invention is: Formula I: (SEQ ID NO: 1) Where X 1 represents Gly or Ala; X 2 represents Leu, Ala or Met; X 3 represents Ile or Val, X 4 represents Ser, Thr, Ala, Val, Ile or Leu, X 5 represents Ser, Thr or Ala, X 6 represents Leu, Ala, Val, Ile, Met or Phe;
- the line connecting the two Cys represents a disulfide bond, Having an amino acid sequence represented by Where Formula II: In the formula, a line connecting two Cys represents a disulfide bond.
- cyclic peptide (SEQ ID NO: 3) consisting of the amino acid sequence represented by The amino acid sequence has no peptide bond other than the amino acids constituting the amino acid sequence, A cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof.
- X 1 represents Gly
- X 3 is preferably a cyclic peptide (SEQ ID NO: 2) representing Ile.
- the cyclic peptide of the present invention has an amino acid sequence represented by the formula (I): (SEQ ID NO: 3) In the formula, a line connecting two Cys represents a disulfide bond.
- a cyclic peptide consisting of the amino acid sequence represented by The amino acid sequence represented by the formula (II) is a cyclic part of CNP (hereinafter sometimes referred to as CNP-17).
- Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly which is a human wild-type CNP (hereinafter sometimes referred to as CNP-22) -Ser-Met-Ser-Gly-Leu-Gly-Cys (SEQ ID NO: 4), the peptide is a peptide from the 6th Cys to the 22nd Cys counting from the N-terminus of human wild-type CNP. Applicable.
- amino acid sequence represented by formula (II) (SEQ ID NO: 3) can be excluded from the peptide consisting of the amino acid sequence represented by formula (I) (SEQ ID NO: 1). .
- an amino acid sequence selected from SEQ ID NOs: 60 to 62 (excluding the amino acid sequence of SEQ ID NO: 3), and the amino acid sequence comprises amino acids constituting the amino acid sequence It may be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof without any peptide bond.
- the amino acid sequence has an amino acid sequence selected from SEQ ID NOs: 54 to 56 (except for the amino acid sequence of SEQ ID NO: 3), and the amino acid sequence is composed of amino acids constituting the amino acid sequence. It may be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof without any peptide bond.
- a cyclic peptide having an amino acid sequence selected from SEQ ID NOs: 42 to 47, the amino acid sequence having no peptide bond other than the amino acids constituting the amino acid sequence, or a peptide thereof may be a derivative or a pharmaceutically acceptable salt thereof.
- it has an amino acid sequence selected from SEQ ID NOs: 42 to 47 (excluding the amino acid sequence of SEQ ID NO: 3), and the amino acid sequence is other than the amino acids constituting the amino acid sequence.
- the peptide may be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof.
- a cyclic peptide having an amino acid sequence selected from SEQ ID NOs: 22 to 31 and having no peptide bond other than amino acids constituting the amino acid sequence may be a derivative thereof or a pharmaceutically acceptable salt thereof.
- it has an amino acid sequence selected from SEQ ID NOs: 22 to 31 (excluding the amino acid sequence of SEQ ID NO: 3), and the amino acid sequence is other than the amino acids constituting the amino acid sequence.
- the peptide may be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof.
- the amino acid sequence has an amino acid sequence selected from SEQ ID NOs: 6 to 21, SEQ ID NOs: 32 to 41, SEQ ID NOs: 48 to 53, and SEQ ID NOs: 57 to 59. May be a cyclic peptide or a derivative thereof, or a pharmaceutically acceptable salt thereof, which does not have a peptide bond other than the amino acids constituting the amino acid.
- the cyclic peptide mutants described above may further delete, substitute, or add amino acids in the cyclic peptide as long as they maintain the binding to the CNP receptor or cause structural changes that make it stronger.
- the number may be, for example, 1, 2, 3, 4, 5, 6, or 6 or more as long as it retains CNP activity.
- the homology of the amino acid sequence by the deletion, substitution or addition is a cyclic peptide having 70%, preferably 80%, more preferably 90% or more homology to the above-mentioned mutant cyclic peptide. There may be. Furthermore, as long as activity is retained, the homology is not limited to this range.
- any amino acid constituting the C-ring peptide of the present invention may be substituted with any amino acid as long as it retains the function (activity) of CNP.
- substitutable amino acids include glycine, leucine, aspartic acid, isoleucine, glycine, and serine constituting the C-ring peptide, and these can be substituted with alanine, methionine, valine, threonine, isoleucine, leucine, and phenylalanine. Is possible.
- amino acids that can be substituted with other amino acids can be exemplified as shown in Table 27 and Table 28 below in terms of cyclic peptides (formula I), but are not limited thereto.
- examples of the cyclic peptide in which one amino acid is substituted include SEQ ID NOs: 6 to 21 and the like, but are not limited thereto.
- examples of the cyclic peptide in which 2 amino acids are substituted include SEQ ID NOs: 32 to 41, but are not limited thereto.
- examples of the cyclic peptide in which 3 amino acids are substituted include SEQ ID NOs: 48 to 53, but are not limited thereto.
- examples of the cyclic peptide substituted with 4 amino acids include, but are not limited to, SEQ ID NOs: 57 to 59.
- amino acids can be substituted by appropriately combining the above-described amino acids with the cyclic peptide such as SEQ ID NO: 1 or 60 to 62. It should be noted that other amino acids can be appropriately modified without being constrained by the amino acid positions that may be mutated as described in SEQ ID NO: 1 and the like.
- the present invention may be a mutant as described above, and a derivative thereof. Therefore, any mutant 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.
- it may be a cyclic peptide having at least CNP activity.
- the term “having CNP activity” refers to a case where it has 20% or more binding activity to a natriuretic peptide receptor (eg, GC-A, GC-B).
- the CNP activity can be measured according to a conventional method.
- amino acids constituting this can be modified as appropriate.
- chemical modification of the cyclic peptide of the present invention to amino acids, etc., deletion of some amino acids constituting the cyclic peptide, substitution with other amino acids, and / or addition of new amino acids can be made.
- the cyclic peptide of the present invention includes a derivative of the above-mentioned cyclic peptide.
- a derivative can be used as an active substance as it is, and can also be used as a prodrug.
- the derivative of the present invention can add (modify) or substitute a known substituent to a specific group of an amino acid in a cyclic peptide, for example, a hydrogen atom, a hydroxyl group, a carboxy group, an amino group, an imino group, and the like. It can be obtained by substitution with a known substituent.
- a known substituent include, but are not limited to, chemical modifications such as sugar chain addition, acetylation, phosphorylation, and lipid addition to amino acids in the cyclic peptide.
- addition (modification) or substitution to an amino acid group in the cyclic peptide may occur simultaneously in one or more groups or more.
- substituents are not particularly limited as long as they can be substituted with respect to the above groups, and known substituents can be used.
- protective groups such as BOC can be used. Of course, it is included.
- the C-terminal group of one Cys of the cyclic peptide may be replaced with —COOR 1 , —CONHR 1 or —CONR 1 2 instead of —COOH, and / or the N-terminal group of the other Cys of the cyclic peptide.
- NH 2 may be replaced with —NHC (O) R 1 or —N (C (O) R 1 ) 2 .
- R 1 is independently a branched or straight chain hydrocarbon group having 1 to 20 carbon atoms, an alkylene glycol chain, or a sugar chain, each time it appears.
- the carbon number of R 1 is preferably 1 to 10, more preferably 1 to 5, and further preferably 1 to 2.
- the pharmaceutically acceptable salt is not particularly limited, and examples of the cyclic peptide or derivative of the present invention include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. And salts with basic, neutral, or acidic amino acids.
- the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, aluminum salt and ammonium salt.
- salts with organic bases include, for example, salts with alkylamines such as trimethylamine and triethylamine; salts with heterocyclic amines such as pyridine and picoline; alkanolamines such as ethanolamine, diethanolamine and triethanolamine And salts with cycloalkylamines such as cyclohexylamine and dicyclohexylamine; salts with alkylenediamine derivatives such as N, N′-dibenzylethylenediamine, and the like.
- salts with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- salts with organic acids include salts with monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid; salts with polyvalent carboxylic acids such as fumaric acid, oxalic acid and maleic acid; And 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.
- monocarboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid
- salts with polyvalent carboxylic acids such as fumaric acid, oxalic acid and maleic acid
- oxycarboxylic acids such as tartaric acid, citric acid, succinic acid and malic acid
- salts with sulfonic acids such as methanes
- salts with neutral amino acids include, for example, salts with glycine, valine, leucine and the like
- salts with basic amino acids include, for example, arginine, lysine, ornithine and the like.
- Suitable salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like.
- a cyclic peptide consisting of the amino acid sequence represented by the formula (I) or a pharmaceutically acceptable salt thereof is preferable. That is, the amino acid sequence represented by formula (I) is preferably not substituted.
- the production method of the cyclic peptide, derivative, and pharmaceutically acceptable salt thereof of the present invention is not particularly limited, and for example, a known chemical synthesis method or genetic engineering synthesis method can be used.
- the amino acid sequence When the amino acid sequence is synthesized by a chemical synthesis method, it may be synthesized by any chemical synthesis method, and can be synthesized by a known peptide synthesis method, for example, a solid phase synthesis method or a liquid phase synthesis method. . In the synthesis, a commercially available peptide synthesizer (eg, Shimadzu Corporation: PSSM-8) may be used.
- PSSM-8 a commercially available peptide synthesizer
- the disulfide bond in the amino acid sequence is not particularly limited, but can be formed, for example, by DMSO oxidation method, iodine oxidation method or the like.
- a free sulfhydryl group or a sulfhydryl group protected with a protecting group can be treated with DMSO or iodine (I 2 ) to form an intramolecular disulfide bond, resulting in a cyclic peptide. .
- protecting group examples include 4-methylbenzyl group (Bzl (4Me)), trityl group (Trt), tert-butyl group, N- (acetyl) aminomethyl group (Acm) and the like. Further, deprotection can be carried out by an appropriate treatment corresponding to these protecting groups, for example, by treating a 4-methylbenzyl group with a strong acid and an N- (acetyl) aminomethyl group with iodine. it can.
- derivatization of the cyclic peptide is performed as necessary to obtain a derivative.
- the derivatization can be performed by a known method.
- a pharmaceutically acceptable salt is produced by performing salt exchange of the cyclic peptide or derivative as necessary.
- Salt exchange can be performed, for example, by contacting the cyclic peptide or derivative with the desired acid or base.
- a DNA fragment encoding the amino acid sequence represented by formula (I) is prepared.
- a primer designed to synthesize a predetermined DNA region using a vector containing a full-length human CNP gene as a template can be performed by amplifying a DNA fragment by the PCR method.
- DNA fragments may be chemically synthesized.
- the amplified DNA fragment is ligated to an appropriate vector to obtain a recombinant vector for protein expression.
- the recombinant vector for protein expression is taken into the target cell, and the taken-in cell is selected.
- the protein produced from the cells protein consisting of the amino acid sequence represented by the formula (I)
- Disulfide bond formation, derivatization, and salt formation in the recovered protein can be performed as described above.
- confirmation that the compound, such as the target cyclic peptide, was obtained can be performed by well-known methods, such as reverse phase HPLC and mass spectrometry, for example.
- the presence or absence of CNP activity of the obtained compound can be easily confirmed by known means, for example, by confirming cGMP production activity in NPR-B receptor-expressing cells. Can do.
- the term “external preparation” means an agent applied to the skin and mucous membrane, which is not limited to uses such as medicines, quasi drugs, skin care products, and cosmetics.
- the external preparation of the present invention comprises one or more cyclic peptides and / or derivatives thereof as described above and / or pharmaceutically acceptable salts thereof.
- cyclic peptides there is no particular upper limit to the kind of cyclic peptide to be mixed, but about 2 to 3 kinds are preferable from the viewpoint of preparation cost and simplicity.
- SEQ ID NOs: 50, 58, 15 and 9 examples thereof include SEQ ID NOs: 50, 58, 15 and 9, but are not limited to these as long as they do not impair the effects of the present invention, and these cyclic peptides may be combined as appropriate according to the application target and the like. it can.
- the external preparation of this invention is not specifically limited, For example, it can be used for the following uses, In each case, the outstanding effect which is not before is exhibited.
- the external preparation of the present invention is not particularly limited in any application, and can be used as a pharmaceutical, a quasi-drug and / or a cosmetic depending on its medicinal effect and efficacy.
- Dermatitis therapeutic agent dermatitis preventive agent
- the external preparation of the present invention can be a dermatitis therapeutic agent and / or a dermatitis preventive agent.
- the external preparation of the present invention When applied on the skin or mucous membrane of a subject suffering from dermatitis, the external preparation of the present invention causes or may cause itchiness, pain (pain), heat, tension, erythema, infiltration, papules. Objective dermatitis symptoms can be improved while rapidly relieving or eliminating various perceptible symptoms and conditions such as lichenification, crusting, leaching and skin dryness. Moreover, the external preparation of this invention does not produce irritation in an application site
- the cyclic peptide of the present invention has a structure advantageous for binding to its receptor, NPR-B receptor, compared to CNP. As a result, it is possible that the NPR-B receptor in the vicinity of the affected part can be bound more rapidly and the binding time is longer. In addition, by binding to the NPR-B receptor in the vicinity of the affected area relatively quickly, it is possible to prevent the cyclic peptide from diffusing outside the affected area due to blood flow or the like. It is thought that it can be stopped.
- the external preparation of the present invention not only suppresses or prevents inflammation of dermatitis but also has an action of restoring or maintaining the skin barrier function.
- the barrier function of the skin has a function to prevent irritation from the external environment and bacteria from entering the skin and a moisturizing function.
- the external preparation of the present invention has the effect of preparing the texture and moisturizing the skin. Therefore, the action of recovering and maintaining the barrier function of the skin of the external preparation is also apparent.
- the external preparation of the present invention is also effective for skin symptoms such as comedones, sore acne, sore acne, pustules, cysts and nodules.
- Such perceptible symptoms, amelioration of the state, and disappearance effect of the external preparation of the present invention generally develop within 10 minutes, preferably within 5 minutes, more preferably within 3 minutes after application.
- the external preparation of the present invention has a satisfactory therapeutic effect such as dermatitis causing steroid dermatosis or dermatitis that cannot be treated with other dermatitis drugs such as steroids and tacrolimus. It is also possible to treat dermatitis that is not possible, resistant to those formulations, unsuitable or undesirable.
- dermatitis that is not possible, resistant to those formulations, unsuitable or undesirable.
- steroid external preparations that have been widely used in the past, if the external application was stopped, there was a serious problem that it immediately returned to the severity before the external application or worsened before the external application due to a rebound phenomenon.
- the external preparation of the present invention does not have such a problem as the rebound phenomenon.
- Dermatitis is a disease that generally causes inflammation on the skin or mucous membranes. Dermatitis usually includes erythema, infiltrating erythema, papules, blisters, pustules, infiltration, ligation, desquamation and other chronic eczema symptoms, lichenification, pigmentation and other chronic eczema symptoms, scales, crusts (Scab) With one or more symptoms selected from the group consisting of adhesion, curettage, scratching scars, prurigo nodules, erosion, edema, tingling, and scaly.
- the dermatitis is not particularly limited as long as it is a disease accompanied by inflammation on the skin or mucous membrane.
- chronic eczema allergic eczema, eczema such as childhood dry eczema, atopic dermatitis
- allergic Contact dermatitis contact dermatitis such as primary irritant contact dermatitis
- seborrheic dermatitis sebum-deficient dermatitis
- stasis dermatitis allergic urticaria (eg food Urticaria such as physical urticaria, drug-induced urticaria), non-allergic urticaria (eg, physical urticaria, sunlight urticaria, choline urticaria); insect bites; drug eruption; psoriasis vulgaris, drops Psoriasis such as psoriasis, psoriatic erythroderma, pustular psoriasis
- the external preparation of the present invention is particularly effective against eczema, atopic dermatitis, contact dermatitis, seborrheic dermatitis, insect bite, allergic or non-allergic urticaria, psoriasis, preferably eczema, It exhibits excellent effects against atopic dermatitis, contact dermatitis, insect bites and photodermatoses, and more preferably against eczema and atopic dermatitis. Therefore, the external preparation of the present invention can be used for the purpose of treating or preventing at least one dermatitis selected from the above group.
- the external preparation of the present invention can be a material for cosmetic or skin care product.
- the external preparation of the present invention moisturizes the application site and exerts a moisturizing effect to prevent dryness, as well as rough skin and sensitive skin.
- the stratum corneum is present at the application site, the effect of adjusting the texture of the application site is exhibited.
- moderate elasticity and flexibility are imparted to and maintained on the skin and mucous membranes, the skin becomes soft, and the skin and mucous membranes are crushed and tightened.
- wrinkles and sagging including fine lines and large wrinkles are improved at the application site, and dullness and spots become inconspicuous. Further, since dullness and blotches are not noticeable, a whitening effect is obtained as a result. Furthermore, photosensitivity can be prevented.
- the external preparation of the present invention is not particularly limited for the purpose of maintaining or improving the state of the skin and / or mucous membrane, but includes, for example, dry skin, rough skin, sensitive skin, rough lips, sagging, fine lines and fine lines. Prevention, progression or improvement of skin, maintenance of skin or mucous membrane state, prevention of photosensitivity, anti-aging and whitening, or at least selected from the above effects It can be used for the purpose of obtaining one kind of effect.
- rough skin includes a rash, a moistness, a crack, a redhead, an acne, a diaper rash, a sore, a crotch, and a razor.
- the specific use of the external preparation of the present invention as a material for cosmetics or skin care products is not particularly limited.
- lotion, emulsion, serum, cream, cold cream, gel, mask, pack, powder Makeup cosmetics such as hand cream, body powder, after-shave lotion, pre-shave lotion, perfume, deodorant, foundation, white powder, eye shadow, eyeliner, mascara, eyebrow, teak, makeup base, lipstick, lip balm, nail color, etc.
- shampoos, rinses, conditioners, hair color, hair tonics set agents, hair cosmetics such as permanent agents, body cleansing agents such as face wash, cleansing, body soap, hand soap, bath preparations (bath preparations), Raised It is.
- the above-mentioned effects of the external preparation of the present invention are rapidly manifested, and generally vary within 10 minutes, preferably within 5 minutes, more preferably within 3 minutes after application, depending on the type of the effect.
- the above-described effects of the external preparation of the present invention last for a relatively long time and vary depending on the type of the effect, but generally 4 hours or more after the effect is exerted, preferably 8 hours or more, more preferably 24 hours or more. continue.
- the external preparation of the present invention can be an antipruritic agent.
- the external preparation of the present invention is suitable as an antipruritic agent because it exhibits an excellent antipruritic effect at the application site when applied onto the skin or mucous membrane.
- the antipruritic effect of the external preparation of the present invention as described above generally develops within 10 minutes, preferably within 5 minutes, more preferably within 3 minutes after application.
- the external preparation of the present invention includes alopecia therapeutic agent, alopecia preventive agent, hair restorer, hair growth agent and / or Or it can be a hair loss preventing agent.
- the external preparation of the present invention When applied to a site such as a hair loss site or a hair growth site, the external preparation of the present invention has the effect of preventing hair loss and hair loss at the application site, promoting hair growth or hair growth, and thickening the hair.
- there are effects such as hair restoration effect, hair growth promotion effect, thinning hair improvement / prevention. In this case, the hair that grows tends to be hard and tends to be non-white hair.
- these effects are expressed relatively early compared to other active ingredients conventionally used in therapeutic agents for alopecia, such as CNP, and the obtained effects are also remarkable.
- the external preparation of the present invention has an effect of improving and preventing dermatitis as described above. Therefore, the inflammation of the skin accompanying alopecia can be improved or prevented. Such an effect is particularly advantageous when alopecia is aggravated due to the skin condition of the application site such as the scalp.
- the external preparation of the present invention when applied to the skin as described above, exhibits a moisturizing effect and an effect of adjusting the texture at the application site. It can remove dandruff and itching, suppress these occurrences, moisturize the hair and scalp, improve drying, prevent seborrhea, and keep the scalp and hair healthy. Moreover, a seborrheic state can be improved.
- the external preparation of the present invention has perceptible symptoms, amelioration of the state, and disappearance effect as described above. This reduces the burden on the subject (patient) and improves the patient's QOL. Furthermore, it is possible to prevent the patient from damaging the affected part, such as touching or scratching the affected part with concern about itching and pain, and as a result, it is possible to prevent the deterioration of the skin condition causing alopecia.
- alopecia therapeutic agent When the external preparation of the present invention is used as an alopecia therapeutic agent or an alopecia preventive agent, applicable alopecia is not particularly limited, and examples thereof include alopecia as described below. It can be used for the treatment or prevention of more than one species.
- Alopecia without scars or skin lesions Alopecia areata, male pattern alopecia, seborrheic alopecia, dwarf alopecia, female pattern alopecia, gestational alopecia, malignant alopecia, senile Alopecia, frontal alopecia, multiple alopecia, serpentine alopecia, drug-induced alopecia, cancer chemotherapeutic alopecia and alopecia due to radiation exposure, traumatic / mechanical alopecia, nutritional disorders / metabolic disorders Alopecia associated with, alopecia associated with endocrine abnormalities, resting alopecia (postpartum alopecia, alopecia after high fever))
- Congenital alopecia Diffuse hair loss, congenital alopecia, hair loss in hereditary syndrome, localized hair loss, nevus, aplasia cutis, congenital triangular hair loss
- the external preparation of the present invention is particularly suitable for acquired alopecia, preferably for alopecia without scars or skin lesions, more preferably alopecia areata, androgenetic alopecia, fat.
- Alopecia areata, fertility alopecia, female pattern alopecia, gestational alopecia, malignant alopecia, senile alopecia, frontal alopecia, multiple alopecia, serpentine alopecia, drug alopecia, cancer
- Rhinitis therapeutic agent and / or rhinitis preventive agent The external preparation of the present invention can be a rhinitis therapeutic agent and / or a rhinitis preventive agent.
- Rhinitis is a disease caused by inflammation of the mucous membrane of the nasal cavity and / or sinuses, and causes symptoms such as pruritus as well as main symptoms such as nasal congestion, rhinorrhea, and sudden sneezing.
- rhinitis includes not only rhinitis accompanied by inflammation of the nasal mucosa in a narrow sense but also sinusitis accompanied by inflammation of the sinus mucosa.
- the external preparation of the present invention can improve or prevent various symptoms associated with rhinitis such as nasal congestion, rhinorrhea, sneezing and pruritus when applied to the nasal mucosa and / or sinus mucosa.
- these effects appear rapidly and have a long duration as compared with a rhinitis therapeutic agent containing CNP having a tail.
- Such an effect of the external preparation of the present invention on rhinitis generally develops within 8 minutes after application, preferably within 5 minutes, more preferably within 3 minutes. More particularly preferably, it is expressed within 1 minute.
- the effect with respect to rhinitis of the external preparation of the present invention as described above generally lasts for 4 hours or more, preferably 8 hours or more, more preferably 24 hours or more after the onset of the effect.
- rhinitis is not particularly limited.
- infectious rhinitis including acute rhinitis and chronic rhinitis; complex type (flower Hypersensitivity) Rhinitis, rhinorrhea, congestive rhinitis, hypersensitivity noninfectious rhinitis including edema and dry rhinitis; physical rhinitis, irritant rhinitis including chemical rhinitis and radiation rhinitis; and atrophic Rhinitis and characteristic granulomatous rhinitis; including sinusitis such as acute sinusitis, chronic sinusitis (pyremic), eosinophilic sinusitis, sinus mycosis, etc. It can be used for treatment or prevention purposes.
- rhinitis examples include allergic rhinitis including perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis including vasomotor (essential) rhinitis and eosinophilia rhinitis. And so on.
- allergic rhinitis examples include perennial allergic rhinitis and seasonal allergic rhinitis, and non-allergic rhinitis including vasomotor (essential) rhinitis and eosinophilia rhinitis. And so on.
- rhinorrhea examples include rhinitis, cold inhalation rhinitis, and senile rhinitis.
- congestive rhinitis examples include drug-induced rhinitis, psychogenic rhinitis, gestational rhinitis, endocrine rhinitis and cold rhinitis.
- edema type rhinitis examples include aspirin hypersensitivity rhinitis.
- the external preparation of the present invention is particularly preferable for hypersensitivity non-infectious rhinitis, irritant rhinitis and sinusitis, preferably for hypersensitivity non-infectious rhinitis and chronic sinusitis.
- the external preparation of the present invention can be used for the purpose of treating or preventing at least one rhinitis selected from the above group.
- the external preparation of the present invention has the effects as described above, and therefore, it can be used for any of sneezing / nasal rhinitis, nasal rhinitis and full rhinitis. it can. Furthermore, the external preparation of the present invention exhibits an effect of improving symptoms even for rhinitis that is difficult to treat with conventionally used rhinitis therapeutic agents such as steroid drugs.
- the external preparations of the present invention can also be used for uses other than those described above for the purpose of the effect of the cyclic peptide.
- the external preparation of the present invention may mainly have effects other than the effects of the cyclic peptide.
- the cyclic peptide of the present invention, its derivative and / or pharmaceutically acceptable salt is used for the purpose of assisting the main effect of the external preparation or adding an effect other than the main effect.
- Examples of such applications include, but are not limited to, deodorization, antiperspiration, hair removal, washing, blood circulation promotion / flavoring, UV damage prevention, UV protection, bactericidal, antiseptic, antioxidant, transdermal absorption promotion, etc. Can be mentioned.
- the topical preparation of the present invention is locally administered to a target site (for example, an affected area) of the skin or mucous membrane, whereby a cyclic peptide as an active ingredient, its derivative and / or pharmaceutically acceptable.
- a target site for example, an affected area
- a cyclic peptide as an active ingredient, its derivative and / or pharmaceutically acceptable.
- the effect of a simple salt can be more reliably and rapidly expressed in the vicinity of the application site.
- Such an external preparation is not particularly limited, and can be, for example, an external preparation, eye drops, ear drops, nasal drops, oral preparations, or suppositories.
- the external preparation of the present invention is a dermatitis therapeutic agent, dermatitis preventive agent, antipruritic agent, skin care product, alopecia therapeutic agent, alopecia preventive agent, hair restorer or hair growth agent, An agent is preferred.
- the external preparation of the present invention is a rhinitis therapeutic agent and / or a rhinitis preventive agent, it is preferably a nasal drop.
- an eye drop is preferable.
- the external preparation of the present invention is not particularly limited when it is an external preparation, but it can be, for example, an external solid preparation, external preparation, spray, ointment, emulsion, cream, gel, or patch.
- An external solid preparation is a solid preparation for application or application to the skin or the like.
- Examples of such external solid preparations include powdery external powders.
- the external liquid preparation is a liquid preparation for application to the skin and the like. Examples of such external liquid preparations include lotions and liniments.
- a spray is a preparation in which an active ingredient is sprayed onto the skin in the form of a mist, powder, foam, paste, or the like. Examples of such sprays include external aerosols and pump sprays.
- An ointment is a semisolid preparation that is applied to the skin and in which an active ingredient is dissolved or dispersed in a base. Further, the ointment may be a lip balm for applying to the local area such as lips.
- a cream is a semi-solid preparation emulsified in an oil-in-water or water-in-oil type that is applied to the skin.
- a gel is a gel-like preparation applied to the skin.
- the gel agent include an aqueous gel agent and an oily gel agent.
- a patch is a preparation to be applied to the skin. Examples of the patch include a tape and a poultice.
- Nasal drops are formulations that are administered to the nasal cavity or nasal mucosa. Examples of the nasal drops include nasal powders and nasal drops. Of these, nasal drops are preferred.
- the external preparation of the present invention contains at least the cyclic peptide of the present invention and / or a derivative thereof and / or a pharmaceutically acceptable salt thereof as described above.
- the external preparation of the present invention contains a cyclic peptide and / or a derivative thereof and / or a pharmaceutically acceptable salt thereof, for example. 0.0001 to 1000000 ⁇ g / g, preferably 0.001 to 10,000 ⁇ g / g, more preferably 0.01 to 1000 ⁇ g / g, and still more preferably 0.1 to 100 ⁇ g / g. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / g and 1 to 500 ⁇ g / g.
- the external preparation of the present invention contains, for example, a cyclic peptide and / or a derivative thereof and / or a pharmaceutically acceptable salt thereof in the stock solution of the spray. , 0.0001 to 1000000 ⁇ g / mL, preferably 0.001 to 10,000 ⁇ g / mL, 0.01 to 1000 ⁇ g / mL, more preferably 0.1 to 100 ⁇ g / mL, even more preferably 1 to 100 ⁇ g / mL . In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention contains a cyclic peptide and / or a derivative thereof and / or a pharmaceutically acceptable salt thereof, for example, 0.0001 to 1000000 ⁇ g / mL, Preferably, it is contained at a concentration of 0.001 to 10,000 ⁇ g / mL, more preferably 0.01 to 1000 ⁇ g / mL, still more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention is a cyclic peptide and / or a derivative thereof and / or a nasal drop liquid (nasal drop).
- These pharmaceutically acceptable salts are, for example, 0.001 to 10,000 ⁇ g / mL, more preferably 0.01 to 1000 ⁇ g / mL, preferably 0.1 to 100 ⁇ g / mL, and more preferably 1 to 100 ⁇ g / mL. Contain at a concentration of In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention can be formulated using methods and constituent materials known to those skilled in the art regardless of the dosage form as described above.
- the constituent material that can be used is not particularly limited.
- thickening gelling agent oil component, alcohol, fatty acid, organic acid, ultraviolet absorber, ultraviolet scattering agent, powder, pigment, surfactant, polyvalent
- examples include alcohols / sugars, polymers, physiologically active ingredients, solvents, antioxidants, chelating agents, fragrances, preservatives, and animal and plant extracts.
- the thickening gelling agent various gelling agents of organic and inorganic compounds can be used.
- the gelling agent for inorganic compounds include hydrous or water-absorbing silicates such as aluminum silicate (eg bentonite), magnesium silicate-aluminum, colloidal silica, and the like.
- the gelling agent for organic compounds natural, semi-synthetic or synthetic polymers can be used.
- Natural and semi-synthetic polymers include, for example, polysaccharides such as cellulose, starch, tragacanth, gum arabic, xanthan gum, agar, gelatin, alginic acid and its salts (such as sodium alginate and its derivatives), lower alkyl cellulose (such as methylcellulose or ethylcellulose) ), Carboxy- or hydroxy-lower-alkyl cellulose (for example, carboxymethyl cellulose or hydroxypropyl cellulose) and the like.
- polysaccharides such as cellulose, starch, tragacanth, gum arabic, xanthan gum, agar, gelatin, alginic acid and its salts (such as sodium alginate and its derivatives), lower alkyl cellulose (such as methylcellulose or ethylcellulose) ), Carboxy- or hydroxy-lower-alkyl cellulose (for example, carboxymethyl cellulose or hydroxypropyl cellulose) and the like.
- Examples of the synthetic polymer include carboxyl vinyl polymer, sodium polyacrylate, (vinyl methyl ether / ethyl maleate) copolymer, polymethacrylate, polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid or polymethacrylic acid.
- commercially available gelling agents such as Lubragel NP, Lubragel CG, Lubragel DV, Lubragel MS, Lubragel OIL, Lubragel TW, Lubragel DS, etc. (Ashland) may be used as the gel agent.
- oil component for example, various oil phase components of ester, ether, hydrocarbon, silicone, and fluorine, animal and vegetable oils and their hardened oils, and naturally derived waxes can be used.
- ester-based oil phase component examples 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 , Isoaralkyl neopentanoate, glyceryl tri (capryl / caprate), trimethylo
- Glyceryl tricaprylate glyceryl triundecylate, glyceryl triisopalmitate, glyceryl triisostearate, octyldodecyl neopentanoate, isostearyl octanoate, octyl isononanoate, hexyldecyl neodecanoate, octyldodecyl neodecanoate, isocetyl isostearate, isostearic acid isostearate Stearyl, octyldecyl isostearate, polyglycerol oleate, polyglycerol isostearate, dipropyl carbonate, dialkyl carbonate (C12-18), triisocetyl citrate, triisoaralkyl citrate, triisooctyl citrate, lauryl lactate, lactic acid Myristyl, cetyl lactate
- hydrocarbon oil phase component examples include squalane, liquid paraffin, ⁇ -olefin oligomer, isoparaffin, ceresin, paraffin, liquid isoparaffin, solid paraffin, polybutene, microcrystalline wax, petrolatum and the like.
- silicone-based oil phase components include dimethylpolysiloxane, methylphenylpolysiloxane, methylcyclopolysiloxane, octamethylpolysiloxane, decamethylpolysiloxane, dodecamethylcyclosiloxane, methylhydrogenpolysiloxane, polyether-modified organo Polysiloxane, dimethylsiloxane / methylcetyloxysiloxane copolymer, dimethylsiloxane / methylstearoxysiloxane copolymer, alkyl-modified organopolysiloxane, terminal-modified organopolysiloxane, amino-modified silicone oil, amino-modified organopolysiloxane, dimethiconol, Examples thereof include silicone gel, acrylic silicone, trimethylsiloxysilicic acid, silicone RTV rubber and the like.
- fluorinated oil phase component examples include perfluoropolyether, fluorine-modified organopolysiloxane, fluorinated pitch, fluorocarbon, fluoroalcohol, and fluoroalkyl / polyoxyalkylene co-modified organopolysiloxane.
- Animal and vegetable oils and their hardened oils, and naturally occurring waxes include, for example, beef tallow, hardened beef tallow, pork tallow, hardened tallow, horse oil, hardened horse oil, mink oil, orange luffy oil, fish oil, hardened fish oil, egg yolk, Animal and plant oils such as jojoba oil and its hardened oils, avocado oil, almond oil, olive oil, cacao butter, apricot oil, kukui nut oil, sesame oil, wheat germ oil, rice germ oil, rice bran oil, safflower oil, shea butter, large Bean oil, evening primrose oil, camellia oil, corn oil, rapeseed oil, hardened rapeseed oil, palm kernel oil, hardened palm kernel oil, palm oil, hardened palm oil, peanut oil, hardened peanut oil, castor oil, hardened castor oil, sunflower oil , Grape seed oil, jojoba oil, hardened jojoba oil, macadamia nut oil, medhome oil, cottonseed
- higher alcohols examples include lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, behenyl alcohol, 2-ethylhexanol, hexadecyl alcohol, octyldodecanol and the like.
- fatty acids examples 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, 2-ethylhexanoic acid and the like.
- Examples of the ultraviolet absorber include paraaminobenzoic acid, amyl paraaminobenzoate, ethyldihydroxypropyl paraaminobenzoate, glyceryl paraaminobenzoate, ethyl paraaminobenzoate, octyl paraaminobenzoate, octyldimethyl paraaminobenzoate, ethylene glycol salicylate, and salicylic acid.
- Octyl triethanolamine salicylate, phenyl salicylate, butylphenyl salicylate, benzyl salicylate, homomenthyl salicylate, benzyl cinnamate, octyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate, mono-2-diparamethoxycinnamate Glyceryl ethylhexanoate, isopropyl paramethoxycinnamate, diethanolamine salt of paramethoxyhydrocinnamate, diisopropyl diiso Lopylcinnamic acid ester mixture, urocanic acid, ethyl urocanate, hydroxymethoxybenzophenone, hydroxymethoxybenzophenonesulfonic acid and its salt, dihydroxymethoxybenzophenone, dihydroxymethoxybenzophenone sodium disulfonate, dihydroxybenzophenone, dihydroxydimethoxy
- transdermal absorption aid examples include acetic acid, sodium acetate, limonene, menthol, salicylic acid, hyaluronic acid, oleic acid, N, N-diethyl-m-toluamide (N, N-diethyl-3-methylbenzamide), stearin Examples include n-butyl acid, benzyl alcohol, isopropyl myristate, isopropyl palmitate, polypropylene glycol, crotamiton, diethyl sebacate, N-methylpyrrolidone, N-ethylpyrrolidone, lauryl alcohol, and the like.
- powders and pigments examples include red No. 104, red No. 201, yellow No. 4, blue No. 1, black No. 401, pigments such as basic dyes, HC colors, disperse dyes and direct dyes, yellow No. 4 AL lake , Yellow 203 BA lake and other lake pigments, nylon powder, silk powder, urethane powder, silicone powder, polymethyl methacrylate powder, cellulose powder, starch, silicone elastomer spherical powder, polyethylene powder, etc., yellow iron oxide , Red iron oxide, black iron oxide, chromium oxide, carbon black, colored pigments such as ultramarine and bitumen, white pigments such as zinc oxide, titanium oxide, cerium oxide, talc, mica, sericite, kaolin, plate-like barium sulfate, etc.
- pigments such as basic dyes, HC colors, disperse dyes and direct dyes
- yellow No. 4 AL lake Yellow 203 BA lake and other lake pigments
- nylon powder silk powder, urethane powder
- Extender pigments pearl pigments such as titanium mica, barium sulfate, calcium carbonate, magnesium carbonate ,
- Metal salts such as aluminum silicate, magnesium silicate, inorganic powder such as silica, alumina, metals such as aluminum stearate, magnesium stearate, zinc palmitate, zinc myristate, magnesium myristate, zinc laurate, zinc undecylenate
- Examples include soap, bentonite, smectite, and boron nitride.
- shape of these powders spherical, rod-like, needle-like, plate-like, irregular shape, flake-like, spindle-like, etc.
- These powders and pigments are conventionally known surface treatments such as fluorine compound treatment, silicone treatment, silicone resin treatment, pendant treatment, silane coupling agent treatment, titanium coupling agent treatment, oil agent treatment, N-acylated lysine.
- Surface treatment may be performed in advance by treatment, polyacrylic acid treatment, metal soap treatment, amino acid treatment, lecithin treatment, inorganic compound treatment, plasma treatment, mechanochemical treatment, or the like.
- any of an anionic surfactant, a cationic surfactant, an amphoteric surfactant and a nonionic surfactant can be used as appropriate.
- the anionic surfactant include fatty acid soap, ⁇ -acyl sulfonate, alkyl sulfonate, alkyl allyl sulfonate, alkyl naphthalene sulfonate, alkyl sulfate, POE alkyl ether sulfate, alkyl amide sulfate.
- alkyl phosphate POE alkyl phosphate, alkyl amide phosphate, alkyloyl alkyl taurine salt, N-acyl amino acid salt, POE alkyl ether carboxylate, alkyl sulfosuccinate, sodium alkyl sulfoacetate, acyl isethionic acid
- Examples include salts, acylated hydrolyzed collagen peptide salts, and perfluoroalkyl phosphate esters.
- cationic surfactant examples include alkyl trimethyl ammonium chloride, stearyl trimethyl ammonium chloride, stearyl trimethyl ammonium bromide, cetostearyl trimethyl ammonium chloride, distearyl dimethyl ammonium chloride, stearyl dimethyl benzyl ammonium chloride, behenyl trimethyl ammonium bromide, Benzalkonium chloride, behenic acid amidopropyldimethylhydroxypropylammonium chloride, stearic acid diethylaminoethylamide, stearic acid dimethylaminopropylamide, lanolin derivative quaternary ammonium salts, and the like.
- tertiary amines such as fatty acid amide dialkylamine, and its salt are also mentioned.
- amphoteric surfactants include carboxybetaine type, amide betaine type, sulfobetaine type, hydroxysulfobetaine type, amide sulfobetaine type, phosphobetaine type, aminocarboxylate type, imidazoline derivative type, and amidoamine type amphoteric types.
- a system surfactant is mentioned.
- Nonionic surfactants include, for example, propylene glycol fatty acid esters, glycerin fatty acid esters, polyglycerin fatty acid esters, sorbitan fatty acid esters, POE sorbitan fatty acid esters, POE sorbitol fatty acid esters, POE glycerin fatty acid esters, POE alkyl ethers, POE fatty acid esters.
- POE hydrogenated castor oil POE castor oil, POE / POP copolymer, POE / POP alkyl ether, polyether-modified silicone lauric acid alkanolamide, alkylamine oxide, hydrogenated soybean phospholipid, hydroxylated soybean phospholipid, polymer System surfactants, biosurfactants and the like.
- Natural surfactants can also be used, and examples of such surfactants include lecithin, saponin, and sugar surfactants.
- polyhydric alcohol and sugar examples include ethylene glycol, diethylene glycol, polyethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, glycerin, diglycerin, polyglycerin, 3-methyl-1,3-butanediol, 1,3 -Butylene glycol, sorbitol, mannitol, raffinose, erythritol, glucose, sucrose, fructose, xylitol, lactose, maltose, maltitol, trehalose, alkylated trehalose, mixed isomerized sugar, sulfated trehalose, pullulan and the like. These chemically modified compounds can also be used.
- polymer examples include acrylic acid ester / methacrylic acid ester copolymer, vinyl acetate / crotonic acid copolymer, vinyl acetate / crotonic acid / vinyl neodecanate copolymer, methyl vinyl ether maleic acid half ester, T- Butyl acrylate / ethyl acrylate / methacrylic acid copolymer, vinyl pyrrolidone / vinyl acetate / vinyl propionate copolymer, vinyl acetate / crotonic acid copolymer (Rubiset 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 / methacrylic acid An
- Naturally derived polymer compounds such as galactan, gum karaya, gum tragacanth, alginic acid, albumin, casein, curdlan, gellan gum, dextran, glucooligosaccharides, fucose-containing polys
- Physiologically active ingredients include substances that impart some physiological activity to the skin when applied to the skin. For example, whitening, anti-inflammation, anti-aging, UV protection, slimming, squeezing, antioxidant, hair growth / hair growth, hair retention, moisturizing, blood circulation promotion, antibacterial / sterilization, cooling / warming, promotion of wound healing, stimulation relief, Ingredients having effects such as analgesia, cell activation, plant extracts, seaweed extracts, vitamins and derivatives thereof, amino acids, various peptides other than cyclic peptides, biopolymers such as sodium hyaluronate, mucopolysaccharide, ceramide, phytosphingosine, Examples include intercellular lipid components such as cholesterol and phytosterol, or similar components, enzyme components, and the like.
- suitable ingredients include, for example, Ashitaba extract, avocado extract, amateur extract,retea extract, arnica extract, aloe extract, apricot extract, apricot kernel extract, isoflavone, ginkgo biloba extract, fennel extract, turmeric extract, oolong tea extract.
- Ages extract Echinacea leaf extract, Ogon extract, Oat extract, Auren extract, Barley extract, Hypericum extract, Oyster extract, Dutch mustard extract, Orange extract, Cacao extract, Seawater dried product, Seaweed extract, Hydrolyzed elastin, Hydrolyzed wheat Powder, hydrolyzed silk, pumpkin seed extract, chamomile extract, carrot extract, cormorant extract, licorice extract, calcade extract, oyster extract, kiwi extract, kina extract, cuecan Ekisu, guanosine, gardenia extract, kumazasa extract, Clara extract, cranberry extract, walnut extract, grapefruit extract, Clematis extract, chlorella extract, mulberry extract, gentian extract, black tea extract, yeast extract, burdock root extract, rice bran fermentation extract,
- Biopolymers such as deoxyribonucleic acid, mucopolysaccharide, sodium hyaluronate, sodium chondroitin sulfate, collagen, elastin, chitin, chitosan, hydrolyzed eggshell membranes, amino acids, hydrolyzed peptides, sodium lactate, urea, sodium pyrrolidonecarboxylate , Betaine, whey, trimethylglycine, lysine / arginine condensate and other moisturizing ingredients, sphingolipids, ceramides, phytosphingosine, cholesterol, cholesterol derivatives, phytosterol derivatives, phospholipids and other intracellular lipid components or similar , ⁇ -aminocaproic acid, glycyrrhizic acid, ⁇ -glycyrrhetinic acid, lysozyme chloride, guaiazulene, hydrocortisone, tea tree oil, etc., vitamin A and
- antioxidants examples include sodium bisulfite, sodium sulfite, erythorbic acid, sodium erythorbate, dilauryl thiodipropionate, tocopherol, tolylbiguanide, nordihydroguaiaretic acid, parahydroxyanisole, butylhydroxyanisole, dibutylhydroxyl
- plant extracts having an antioxidant effect such as toluene, ascorbyl stearate, ascorbyl palmitate, octyl gallate, propyl gallate, carotenoid, flavonoid, tannin, lignan, saponin, apple extract and clove extract.
- solvent examples include physiological saline, purified water, ethanol, lower alcohol, ethers, LPG, fluorocarbon, N-methylpyrrolidone, fluoroalcohol, volatile linear silicone, and next-generation fluorocarbon.
- the present invention also includes the present invention. It also relates to the use of the inventive cyclic peptides and / or derivatives thereof and / or their pharmaceutically acceptable salts for the preparation of external preparations.
- the method for using the external preparation of the present invention includes applying the above-described external preparation of the present invention to the skin and / or mucous membrane of the subject.
- the target is not particularly limited, and examples thereof include vertebrates such as birds and mammals.
- mammals include, for example, laboratory animals such as rodents and rabbits such as mice, rats, gerbils, hamsters and guinea pigs, domestic animals such as pigs, cows, goats, horses, sheep and minks, and pets such as dogs and cats.
- Primates such as humans, monkeys, cynomolgus monkeys, rhesus monkeys, marmosets, orangutans and chimpanzees. Of these, human is particularly preferable. On the other hand, humans can also be excluded from subjects.
- the skin and / or mucous membrane of the subject to which the external preparation is applied may be the skin or mucous membrane of any part of the subject, for example, the head (scalp), face, neck, arm, trunk, arm, hand. It can be applied to skin or mucous membranes such as feet.
- the more specific usage method of the external preparation of this invention is as follows.
- the application frequency is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day.
- the dose is not particularly limited.
- the total amount of the cyclic peptide of the present invention and derivatives thereof and pharmaceutically acceptable salts thereof is 0.0001 to 1000000 ⁇ g / mL, preferably 0.
- 0.001 to 10,000 ⁇ g / mL more preferably 0.01 to 1000 ⁇ g / mL, still more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention When the external preparation of the present invention is used as an antipruritic agent, it can be directly applied to the intended skin and / or mucosal site.
- the frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day.
- the dose is not particularly limited.
- the total amount of the cyclic peptide of the present invention and derivatives thereof and pharmaceutically acceptable salts thereof is 0.0001 to 1000000 ⁇ g / mL, preferably 0.
- 0.001 to 10,000 ⁇ g / mL more preferably 0.01 to 1000 ⁇ g / mL, still more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention When the external preparation of the present invention is used as a cosmetic, it can be directly applied to the skin and / or mucosal site for which the external preparation is intended.
- the frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day.
- the dose is not particularly limited.
- the total amount of the cyclic peptide of the present invention and derivatives thereof and pharmaceutically acceptable salts thereof is 0.0001 to 1000000 ⁇ g / mL, preferably 0.
- 0.001 to 10,000 ⁇ g / mL more preferably 0.01 to 1000 ⁇ g / mL, still more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention is used as a hair loss treatment agent, hair loss prevention agent, hair growth agent or hair growth agent and / or hair loss prevention method
- the external preparation can be directly applied to a target site (for example, a scalp, a hair loss site on the skin).
- the frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day.
- the dose is not particularly limited.
- the total amount of the cyclic peptide of the present invention and derivatives thereof and pharmaceutically acceptable salts thereof is 0.0001 to 1000000 ⁇ g / mL, preferably 0. 0.001 to 10,000 ⁇ g / mL, more preferably 0.01 to 1000 ⁇ g / mL, still more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the external preparation of the present invention can be directly applied to a target site (for example, nasal mucosa).
- the frequency of application is not particularly limited, but is, for example, 1 to 10 times / day, preferably 1 to 5 times / day, and more preferably 1 to 3 times / day.
- the dose is not particularly limited.
- the total amount of the cyclic peptide of the present invention and derivatives thereof and pharmaceutically acceptable salts thereof is preferably 0.001 to 10000 ⁇ g / mL for each nasal cavity once applied.
- it can be 0.01 to 1000 ⁇ g / mL, more preferably 0.1 to 100 ⁇ g / mL, and particularly preferably 1 to 100 ⁇ g / mL. In another embodiment, it may be contained at a concentration of 0.1 to 800 ⁇ g / mL and 1 to 500 ⁇ g / mL.
- the medicament of the present invention includes one or more cyclic peptides of the present invention or derivatives thereof, or pharmaceutically acceptable salts thereof.
- the cyclic peptide of the present invention or a derivative thereof, or a pharmaceutically acceptable salt thereof, like CNP binds to the receptor NPR-B having a guanylate cyclase domain to promote the production of cGMP.
- it is considered to have actions such as diuretic action, vasodilatory action, renin / aldosterone secretion inhibition, sympathetic nerve inhibition, and hypertrophy inhibition.
- these compounds of the present invention are considered to have excellent drug efficacy and efficacy, particularly excellent immediate effect as compared with CNP.
- the medicament of the present invention can be used for the same purpose as a medicament conventionally containing CNP as an active ingredient.
- the disease to which the medicament of the present invention can be applied is not particularly limited.
- various diseases hypertension, unstable angina, acute myocardial infarction, edematous disease, renal failure, heart failure, immune disease , Obesity, metabolic syndrome and the like.
- the pharmaceutical dosage form of the present invention is not particularly limited.
- oral administration such as tablets, capsules, granules, powders, oral solutions, syrups, oral jellys, etc.
- 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 a peptide solid phase synthesis method to form a linear peptide consisting of 17 amino acids. Thereafter, the protecting groups at the first Cys and the 17th Cys from the N-terminal were removed. Thereafter, iodine (I 2 ) treatment was performed to form a cysteine bond between the amino acid residues oxidatively to form a cyclic peptide. The obtained composition containing a cyclic peptide was purified by reverse phase liquid high-performance chromatography (reverse phase HPLC) and then freeze-dried to obtain a purified product of the cyclic peptide as a white powder.
- reverse phase HPLC reverse phase liquid high-performance chromatography
- the solution was made uniform and charged into the mixing kettle. Next, 6.0 g of concentrated glycerin is charged into the mixing kettle, and then 0.44 g of carboxyvinyl polymer (trade name: Carbopol 940, manufactured by Lubrizol Advanced Materials) and xanthan gum (trade name: Celtrol) (T, CP KELCO) 0.08 g of the mixture was added and stirred with a paddle, and these were sufficiently dispersed.
- carboxyvinyl polymer trade name: Carbopol 940, manufactured by Lubrizol Advanced Materials
- xanthan gum trade name: Celtrol
- a gel base preparation (C-ring gel preparation) having a concentration of about 1 ⁇ M (about 1.7 ⁇ g / g) was produced.
- gel-based preparations having a C-ring concentration of about 2.0 ⁇ M (about 3.4 ⁇ g / g) and about 5.0 ⁇ M (about 8.5 ⁇ g / g) were produced.
- C-ring gel preparation having a C-ring concentration of about 1 ⁇ M.
- 22 ⁇ l of CNP solution obtained by dissolving 1 mg of human CNP-22 (American Peptide Company) in 1 mL of purified water was uniformly stirred and mixed with 10 g of the gel base obtained above, and then mixed with CNP-22.
- a gel base preparation (CNP gel preparation) having a concentration of about 1 ⁇ M was produced.
- gel-based preparations having CNP-22 concentrations of about 2.0 ⁇ M and 5.0 ⁇ M were produced.
- CNP gel preparation having a CNP concentration of about 1 ⁇ M was used.
- Nasal drops (C-ring nasal drops, Examples) containing a cyclic peptide (C-ring) consisting of the amino acid sequence represented by Formula II and nasal drops containing human CNP (CNP points)
- a nasal preparation and a comparative example were produced as follows.
- C-ring a cyclic peptide consisting of an amino acid sequence represented by Formula II (C-ring) is dissolved in physiological saline, and the concentration is adjusted to obtain a C-ring concentration of about 1 ⁇ mol / l (about 1.7 ⁇ g / g). C ring nose drops were obtained.
- C-ring nasal solution is filled into a quantitative nasal spray container (manufactured by ASONE Co., Ltd.), and the spray amount per one time is adjusted to 100 ⁇ l (0.1 ml), A C ring nose was obtained.
- a CNP nasal solution having a CNP concentration of 1 ⁇ mol / l ( ⁇ M) was obtained, and this was filled into a quantitative nasal spray container (manufactured by ASONE). Further, the spray amount per one time was adjusted to 100 ⁇ l (0.1 ml) to obtain a CNP nasal drop.
- the effect of the C-ring gel preparation was superior to the effect obtained when the CNP gel preparation was applied in any case.
- the C-ring gel preparation was superior in immediate effect and sustainability compared to the CNP gel preparation, and had a stronger antipruritic effect. It was confirmed that these effects could not be obtained with gel base.
- FIG. 1 shows the results of the third day after application by applying the C ring and CNP gel preparation to the lower leg of the patient (P6) who develops psoriasis by the left and right coating method.
- P6 the lower leg of the patient
- FIG. 1 shows the results of the third day after application by applying the C ring and CNP gel preparation to the lower leg of the patient (P6) who develops psoriasis by the left and right coating method.
- P6 the results of the third day after application by applying the C ring and CNP gel preparation to the lower leg of the patient (P6) who develops psoriasis by the left and right coating method.
- the scales became inconspicuous but remained, the erythema and infiltration were only slightly improved, and the effect as high as the C ring was not obtained.
- Ring C is effective against psoriasis compared to conventional topical steroids and vitamin D 3 topical drugs, and requires less effort than biologics, improving treatment satisfaction and QOL. Results were obtained.
- the C ring has a remarkable therapeutic effect and a medicinal effect at a low concentration compared to CNP. Surprisingly, a high therapeutic effect is seen for thick scales that cannot be sufficiently obtained by CNP. Within a short time, and immediate remission maintenance effect was observed. In psoriasis, erythema with thick scales occurs frequently throughout the body, and the scales peel off, so that QOL is severely impaired due to external problems, etc., but C-ring topical therapy improves QOL in patients with psoriasis at an early stage.
- Psoriasis is one of the chronic inflammatory skin diseases and is refractory.
- treatment options for psoriasis include topical steroid and vitamin D 3 topical treatments, UV irradiation, cyclosporine, and etretinate.
- the treatment used in recent years, the biological products used for cases of moderate or higher disease.
- the efficacy of biological products is evaluated, it has been pointed out that there are high cost burdens, concerns about side effects due to long-term use, and the time and effort of subcutaneous injection.
- cases that can be ameliorated by vitamin D 3 alone is small, it is often steroid combination continuation can not be avoided.
- Vitamin D 3 is also used in cases where the skin is thinned due to long-term external use of steroids and etretinate is used, and absorption of external medicines is increased or cases of decreased renal function. When used, attention should be paid to hypercalcemia.
- the C-ring of the present invention not only has an excellent effect as compared with the conventional treatment method, but also eliminates the above-mentioned concerns.
- the C-ring of the present invention has a moisturizing effect on the skin and can adjust the texture, and is effective for improving the skin quality such as whitening, blotting, dullness, anti-aging (sagging, beaming, large wrinkles). At the same time, it was shown to be effective in improving mucosal conditions such as rough lips.
- the site where the C-ring gel formulation was applied showed a marked improvement in the skin quality and its maintenance. Specifically, the skin is smoothed, the skin is moisturized, the skin texture is smoothed, the skin is softened and softened, the skin becomes soft, the drying of the skin is suppressed, the fine lines are inconspicuous, the moisture of the skin, The oil is supplemented and kept, the wrinkles of the eyes are shallow, not noticeable, the skin feels irritated, itching and relieving, the skin is softened, the skin is kept healthy, etc. The effect was significantly recognized at the site where the C-ring gel formulation was applied compared to the site where the CNP gel formulation was applied.
- the cyclic peptide of the present invention has an effect of improving the state of the mucous membrane and has an immediate effect with respect to the above-described effect.
- the C-ring of the present invention moisturizes and keeps the scalp and hair moisturized and keeps supplemental moisture and oil, improving and preventing drying, improving seborrhea, and purifying the scalp and hair. can do.
- it is effective for suppressing itching and dandruff of the scalp, and also for hair, prevention of thinning and hair loss, hair growth, hair loss prevention and prevention, hair growth promotion, hair growth, and hair promotion. It was shown to be effective in improving hair loss and hair restoration after illness and postpartum.
- the bath preparation containing the C-ring of the present invention not only relieves the skin cracks and bruises, but also has an improvement effect on eczema. Furthermore, improvement of skin dryness and skin pain was observed, which was shown to be effective in improving the skin condition.
- a shampoo containing a 4.5.1 C ring was blended and manufactured with the following composition. After A and B were dissolved by heating at 70 ° C., B was added to A and stirred and mixed. Further, C was added at 40 to 35 ° C. with stirring, and the mixture was cooled to room temperature while stirring.
- a treatment containing a C ring was formulated and manufactured with the following composition. After A and B were heated and dissolved at 80 ° C., B was gradually added to A and emulsified while A and B were kept at 80 ° C. while stirring A with a homomixer. Further C was added and cooled to 35 ° C. with stirring.
- the body soap containing a 4.5.3 C ring was mix
- the shampoo, rinse or body soap produced according to the above was used once / day for 14 days, and the results of the subject's scalp and hair or skin condition were evaluated.
- the cases and evaluation are summarized in the following table. Changes in skin condition were evaluated by visual inspection of the subject for scalp dandruff, erythema, etc., and the scalp itching, moist feeling, hair combing, gloss, beam, and stiffness were evaluated by the subject. .
- the use of the hair preparation containing the C-ring of the present invention has an immediate effect of improving scalp itching, erythema and dryness. For thin hair and hair loss, it has been shown that if used continuously for 2 weeks or more, it is effective in improving the symptoms. Furthermore, it was shown that the use of the body soap containing the C-ring of the present invention has an improving effect on dry skin and sensitive skin.
- FIG. 2 is a diagram showing the results before and after applying the C-ring gel preparation to a patient (A11) who develops male type AGA (M type and O type). Seven weeks after the start of application, the stiffness of the hair was strong, the hair became thick, and the hair loss dramatically decreased. As a result, the density of the hair increased and the thin hair became inconspicuous. As for these phenomena, the hair growth and hair-growth effects were more prominent in the gel preparation containing C ring than in CNP. In particular, the hairline was retreated with M-type thin hair, but the hairline was advanced, and hair growth, hair growth, and hair-growth effects on M-type thin hair were confirmed significantly more markedly than CNP.
- the C-ring gel preparation according to the example is applied to the case of the subject having the female pattern alopecia, male pattern alopecia, generalized alopecia, serpentine alopecia, and multiple alopecia
- hair loss was significantly reduced, the hair growth range was expanded, and the growth was rapid.
- the elasticity of the existing hair occurred, and the stiffness became stronger.
- the improvement of the symptom was remarkably improved as compared with the case where the CNP gel preparation according to the comparative example was applied. That is, the C gel preparation was superior in efficacy against the above symptoms as compared to the CNP gel preparation.
- the C-ring gel preparation improved seborrhea, cleaned the scalp, and suppressed dandruff. It also prevented gray hair, grew black hair, and improved thinning hair. Furthermore, it was found that the effect of suppressing itching can be suppressed after 10 minutes, and the effect of immediate effect is high.
- a template structure for examining the binding state between human CNP and the B-type receptor was selected.
- a three-dimensional structure of a complex of rat NPR-A and rat ANP peptide (PDB ID: 1T34) was used.
- Rat NPR-A is a homodimer consisting of A and B chains.
- Such a rat NPR-A has a three-dimensional structure determined by X-ray crystal structure analysis in a state where 21 residues of Cys7 to Arg27 of rat ANP are bound.
- the three-dimensional structure of rat NPR-A was obtained from Protein Data Bank, which is a protein three-dimensional structure database.
- the amino acid identity between human NPR-B and rat NPR-A is 45%.
- the number described with the symbol of an amino acid residue refers to the order counted from the N terminal of the amino acid residue in a peptide. Therefore, for example, in human CNP, the expression “Cys6” means the sixth cysteine counted from the N-terminus of the amino acid sequence of human CNP. The notation of amino acid residues at other positions is the same.
- Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile which is the amino acid sequence of the region from Cys6 to Cys22 of human CNP (CNP-22).
- -Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys SEQ ID NO: 5 was used.
- the region of the CNP peptide model corresponds to the C ring of the present invention.
- the CNP peptide models Cys1, Phe2, Leu4, Lys5, Arg8, Met12, and Gly16 correspond to Cys6, Phe7, Leu9, Lys10, Arg13, Met17, and Gly21 of human CNP (CNP-22), respectively.
- these amino acid residues are considered to be residues that contribute to the activation of NPR-B.
- intramolecular energy was calculated by the Swiss-Pdb viewer's Compute Energy command.
- the intramolecular energy was calculated in units of kilojoule / mol (Kj / mol) based on the total of the bond length between atoms, bond angle, twist, bond energy, and the like.
- 0-2 in the number to be mutated indicates that 0, 1, or 2 amino acids may be mutated arbitrarily in the sequence.
- SEQ ID NOs: 22 to 31, 42 to 47, 54 to 56, and 60 to 62 the case of SEQ ID NO: 3 (that is, the amino acid mutation is 0) can be excluded.
- the effect of applying 1 ⁇ M CNP cyclic peptide is such that an effect equal to or higher than that of CNP of 10 ⁇ M to 50 ⁇ M can be obtained. Furthermore, the newly developed CNP cyclic peptides with some amino acid substitutions are not only highly therapeutic but also immediate, compared to CNP and CNP cyclic peptides without amino acid substitution. The effect of acting at a low concentration was confirmed.
- Test Examples U87 to U88 tests with a CNP cyclic peptide on one side and a cyclic peptide substituted with 4 amino acids on the other side (for example, SEQ ID NO: 58) for the same person) performed by the left-right coating method, SEQ ID NO: 58 It has been confirmed that cyclic peptides such as have an effect of suppressing itching in a few minutes from the start of use against atopic dermatitis, psoriasis and eczema even at a low concentration of only 1 ⁇ g / ml. .
- CNP has an effect equivalent to or better than 10 ⁇ M to 50 ⁇ M.
- CNP or CNP cyclic peptide without amino acid substitution it has only a high therapeutic effect. There was no immediate effect, and the effect of acting at a very low concentration was confirmed.
- the effect of applying 1 ⁇ M CNP cyclic peptide is that CNP has an effect equivalent to or better than 10 ⁇ M to 50 ⁇ M. Compared with CNP or CNP cyclic peptide without amino acid substitution, it has only a high therapeutic effect. There was no immediate effect, and the effect of acting at a very low concentration was confirmed. Furthermore, the newly developed CNP cyclic peptide with partial amino acid substitution has an effect even at a lower concentration, where the effect is not obtained with a CNP cyclic peptide without amino acid substitution, and the effect is immediate and rhinorrhea. Significant improvement in nasal congestion and mucous membrane itchiness and sneezing can be stopped.
- the present invention can be used with peace of mind because even a subject who has strong local irritation due to a conventionally used rhinitis therapeutic agent such as a conventional steroid drug and does not wish to use nasal sprays has no local irritation.
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Abstract
Description
近時、こうしたCNPを利用した治療薬や治療方法がいくつか知られているところであり(特許文献1~5)、中にはCNP環状ペプチドが関節炎に有効であるとの報告もされている(特許文献6)。
したがって、本発明の目的は、新規物質の提供と、従来に比べ薬効、効能の強い新規ペプチド、これを含む医薬や外用剤、特に皮膚炎、鼻炎、脱毛症に対する予防または治療剤や発毛剤、育毛剤、鎮痒剤、化粧料、スキンケア用品などを提供することにある。
すなわち、本発明は以下に関する。
式I:
X1は、GlyまたはAlaを示し、
X2は、Leu、AlaまたはMetを示し、
X3は、IleまたはValを示し、
X4は、Ser、Thr、Ala、Val、IleまたはLeuを示し、
X5は、Ser、ThrまたはAlaを示し、
X6は、Leu、Ala、Val、Ile、MetまたはPheを示し、
2つのCysを結ぶ線は、ジスルフィド結合を表す、
で表されるアミノ酸配列を有し、
当該アミノ酸配列が、当該アミノ酸配列を構成するアミノ酸同士以外のペプチド結合を有さない、
環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
[2]
配列番号60~62から選択される、[1]に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
[3]
配列番号22~31、42~47および54~56から選択される、[1]に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
[4]
配列番号6~21、32~41、48~53および57~59から選択される、[1]に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
[5]
誘導体が環状ペプチド中の水素原子、水酸基、カルボキシ基、アミノ基、イミノ基に対して置換可能な置換基で置換されたものである、[1]~[4]のいずれか一項に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
[4]に記載の環状ペプチド中のアミノ酸の1以上6以下を欠失させるか、他のアミノ酸で置換または付加することにより形成され、かつ前記各式で表される環状ペプチドと同等の機能を有する環状ペプチドもしくはその誘導体またはその薬学的に許容可能な塩。
[7]
[1]~[6]のいずれか一項に記載の環状ペプチドおよび/もしくはその誘導体ならびに/またはこれらの薬学的に許容可能な塩を1種以上含む、外用剤。
[8]
皮膚炎治療剤、皮膚炎予防剤、鎮痒剤、消炎剤、表皮再生促進剤またはスキンケア用品の材料である、[7]に記載の外用剤。
[8]
スキンケア用品が、保湿用および/または肌荒れ防止・改善用および/または敏感肌防止・改善用および/または乾燥肌防止・改善用および/または皮脂改善・ニキビケア用および/または刺激緩和・抗炎症用および/または美白用および/または老化防止用および/またはシワ・たるみおよび/またはくすみ・くま防止・改善用および/または光線過敏症防止・改善用および/または紫外線傷害予防・緩和用および/またはスリミング用および/または皮膚清浄用である、[8]に記載の外用剤。
[10]
入浴剤、身体洗浄剤、頭髪用洗浄剤、リンス・トリートメント、トニック、ヘヤオイル、ヘアローション、スカルプケア剤である、[8]に記載の外用剤。
脱毛症治療剤、脱毛症予防剤、育毛剤および/または発毛剤および/または抜け毛予防剤・防止剤、抜け毛予防化粧料、である、[7]に記載の外用剤。
[12]
フケやかゆみの予防・改善用および/または毛髪、頭皮の乾燥改善・予防用および/または頭皮の脂漏性の改善・予防用のスカルプケア剤である、[7]に記載の外用剤。
[13]
鼻炎治療剤および/または鼻炎予防剤および/または副鼻腔炎治療剤および/または副鼻腔炎予防剤である、[7]に記載の外用剤。
[14]
化粧料である、[7]に記載の外用剤。
[15]
剤形が、固形剤、半固形剤、粉末剤、液剤、スプレー剤、軟膏剤、クリーム剤、乳液剤、ゲル剤または貼付剤である、[7]~[14]のいずれか一項に記載の外用剤。
[16]
[1]~[5]のいずれか一項に記載の環状ペプチド/およびもしくはその誘導体ならびに/またはこれらの薬学的に許容な塩を0.0001~1000000μg/mLの濃度で含む、[7]~[15]のいずれか一項に記載の外用剤。
[17]
医薬品、医薬部外品または化粧品として用いられる、[7]~[16]のいずれか一項に記載の外用剤。
[1]~[5]のいずれか一項に記載の環状ペプチドおよび/もしくはその誘導体ならびに/またはこれらの薬学的に許容可能な塩の外用剤の製造のための使用。
[19]
[7]~[17]のいずれか一項に記載の外用剤を、対象の皮膚および/または粘膜に適用することを含む、外用剤の使用方法。
粘膜が口唇、口腔、鼻腔、眼または膣である、[18]に記載の外用剤の使用方法。
[21]
皮膚炎の治療および/もしくは予防方法、痒みの軽減もしくは消失方法、びらん、潰瘍の治療方法またはスキンケア方法である、[18]に記載の外用剤の使用方法。
[22]
湿疹、アトピー性皮膚炎、接触性皮膚炎、光線過敏症、乾癬、ざ瘡、嚢胞性ざ瘡、脂漏性湿疹、および痒みからなる群から選択される皮膚炎の治療および/または予防方法である、[18]に記載の外用剤の使用方法。
[23]
肌荒れ、敏感肌、乾燥肌、脂性肌、光線過敏症、しわ、たるみ、くすみ、ふけおよび痒みの改善、および予防方法である、[18]に記載の外用剤の使用方法。
[24]
薄毛、脱毛症の治療および/もしくは予防方法ならびに/または発毛方法ならびに/または育毛方法、抜け毛防止および/もしくは予防方法である、[18]に記載の外用剤の使用方法。
[25]
フケやかゆみの防止・予防方法、および/もしくは毛髪、頭皮の乾燥を改善・予防方法、および/もしくは頭皮の脂漏性の予防・改善方法である、[18]に記載の外用剤の使用方法。
[26]
鼻炎、副鼻腔炎の治療および/または予防方法である、[18]に記載の外用剤の使用方法。
[1]~[5]のいずれか一項に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩を1種以上含む、医薬。
[28]
高血圧症、不安定狭心症、急性心筋梗塞、浮腫性疾患、腎不全、心不全、免疫疾患、自己免疫疾患、アレルギー疾患、癌、消化器系疾患、クローン病、潰瘍性大腸炎、肥満、メタボリックシンドロームの治療薬である、[27]に記載の医薬。
さらに、本発明の環状ペプチドは、前記環状ペプチドを変異させたものも含む。すなわち、本発明の変異体は、CNP活性を有する限り、環状ペプチド中のアミノ酸を欠失させるか、他のアミノ酸で置換または付加することより得ることができる。
まず、本発明の環状ペプチド、その誘導体およびこれらの薬学的に許容可能な塩について説明する。
式中、
X1は、GlyまたはAlaを示し、
X2は、Leu、AlaまたはMetを示し、
X3は、IleまたはValを示し、
X4は、Ser、Thr、Ala、Val、IleまたはLeuを示し、
X5は、Ser、ThrまたはAlaを示し、
X6は、Leu、Ala、Val、Ile、MetまたはPheを示し、
2つのCysを結ぶ線は、ジスルフィド結合を表す、
で表されるアミノ酸配列を有し、
当該アミノ酸配列が、当該アミノ酸配列を構成するアミノ酸同士以外のペプチド結合を有さない、環状ペプチドである。
式I:
式中、
X1は、GlyまたはAlaを示し、
X2は、Leu、AlaまたはMetを示し、
X3は、IleまたはValを示し、
X4は、Ser、Thr、Ala、Val、IleまたはLeuを示し、
X5は、Ser、ThrまたはAlaを示し、
X6は、Leu、Ala、Val、Ile、MetまたはPheを示し、
2つのCysを結ぶ線は、ジスルフィド結合を表す、
で表されるアミノ酸配列を有し、
ただし、式II:
で表されるアミノ酸配列からなる、環状ペプチド(配列番号3)を除き、
当該アミノ酸配列が、当該アミノ酸配列を構成するアミノ酸同士以外のペプチド結合を有さない、
環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩である。
X3は、Ileを示す環状ペプチド(配列番号2)であることが好ましい。
さらに、本発明の環状ペプチドは、式(I)で表されるアミノ酸配列が、
式中、2つのCysを結ぶ線は、ジスルフィド結合を表す、
で表されるアミノ酸配列からなる、環状ペプチドであることがより好ましい。式(II)で表されるアミノ酸配列は、CNPの環状部分である(以下、CNP-17と称することがある)。すなわち、ヒト野生型CNP(以下、CNP-22と称することがある)である、Gly-Leu-Ser-Lys-Gly-Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys(配列番号4)であるところ、当該ペプチドは、ヒト野生型CNPのN末端から数えて6番目のCysから22番目のCysまでのペプチドに該当するものである。
回収されたタンパク質におけるジスルフィド結合の形成、誘導体化、塩の形成は、上述したように行うことができる。
また、得られた化合物のCNP活性の有無については、公知の手段によって容易に確認することが可能であり、例えばNPR-B受容体発現細胞におけるcGMP産生活性を試験することにより確認することなどができる。
次に、本発明の外用剤について説明する。なお、本発明において単に「外用剤」という場合、医薬、医薬部外品、スキンケア用品、化粧品などの用途に限定されない、皮膚、粘膜に適用する剤を意味する。
本発明の外用剤は、特に限定されないが、例えば、以下のような用途に用いることができ、それぞれの場合において、従来にない顕著な効果を発揮する。なお、本発明の外用剤は、いずれの用途においても、特に限定されず、その薬効、効能に応じて、医薬品、医薬部外品および/または化粧品として使用することができる。
(1)皮膚炎治療剤、皮膚炎予防剤
本発明の外用剤は、皮膚炎治療剤および/または皮膚炎予防剤であることができる。
本発明の外用剤は、化粧料またはスキンケア用品の材料であることができる。
本発明の外用剤は、皮膚および/または粘膜に適用した場合に、適用部位において潤を与え、保湿効果を発揮して乾燥を防ぐとともに、肌荒れ、敏感肌を防ぐ。適用部位に角質層が存在する場合には適用部位の肌理を整える効果を発揮する。また、皮膚および粘膜に適度な弾力性と柔軟性が付与・保持され、肌が柔らかくなり、皮膚、粘膜にハリが生じ、ひきしまる。また、適用部位において小じわ、大じわを含むしわやたるみが改善され、さらにくすみ、しみが目立たないものとなる。また、くすみ、しみが目立たなくなることから、結果的に美白効果が得られる。さらに光線過敏症を予防することができる。
なお、本明細書中において、肌荒れは、あせも、しもやけ、ひび、あかぎれ、にきび、おしめ(おむつ)かぶれ、ただれ、股ずれおよび剃刀まけを含む。
また、本発明の外用剤の上記効果は、比較的長く持続するものであり、その効果の種類によって異なるが、一般に効果発現後4時間以上、好ましくは、8時間以上、より好ましくは24時間以上持続する。
本発明の外用剤は、鎮痒剤であることができる。
上述したように、本発明の外用剤は、皮膚または粘膜上に適用した際に、適用部位において優れた鎮痒効果を迅速に発揮するため、鎮痒剤として適している。
また、上述したような本発明の外用剤の鎮痒効果は、一般に適用後10分以内、好ましくは、5分以内、より好ましくは3分以内に発現する。
また、本発明の外用剤は、脱毛症治療剤、脱毛症予防剤、育毛剤、発毛剤および/または抜け毛予防剤であることができる。
本発明の外用剤は、脱毛部位または発毛部位等の部位に適用した場合において、適用部位における脱毛・抜け毛を防止するとともに、発毛または育毛を促進し、毛を太くする効果を有する。また適用部位においては、養毛効果、毛生促進効果、薄毛改善・予防などの効果がある。この場合において、発毛する毛髪は硬毛となりやすく、白髪ではない髪となりやすい傾向にある。また、これらの効果は、従来脱毛症治療剤において用いられた他の活性成分、例えばCNPと比較して比較的早期に発現し、得られる効果も顕著である。
(i)瘢痕または皮膚病変を伴わない脱毛症(円形脱毛症、男性型脱毛症、脂漏性脱毛症、粃糠性脱毛症、女性型脱毛症、妊娠性脱毛症、悪性脱毛症、老人性脱毛症、前頭脱毛症、多発性脱毛症、蛇行性脱毛症、薬物による脱毛症、癌化学療法剤性脱毛症及び放射線被爆による脱毛症、外傷性・機械的脱毛症、栄養障害・代謝障害に伴う脱毛症、内分泌異常に伴う脱毛症、休止期脱毛(分娩後脱毛症、高熱後脱毛症))
(iii)瘢痕性脱毛症(皮膚感染症による脱毛、炎症性細胞浸潤による脱毛)
瀰漫性脱毛、先天性無毛症、遺伝性の症候群における脱毛、限局性脱毛、母斑性、aplasia cutis、先天性三角形脱毛
また、本発明の外用剤は、鼻炎治療剤および/または鼻炎予防剤であることができる。
鼻炎は、鼻腔および/または副鼻腔の粘膜の炎症に起因する疾患であり、鼻閉、鼻漏、突発反復性のくしゃみといった主症状の他、掻痒感等の症状を引き起こす。なお、本発明において、「鼻炎」は、狭義の意味での鼻腔粘膜の炎症を伴う鼻炎のみならず、副鼻腔粘膜の炎症を伴う副鼻腔炎も含むものとする。
また、上述したような本発明の外用剤の鼻炎に対する効果は、一般に効果発現後4時間以上、好ましくは、8時間以上、より好ましくは24時間以上持続する。
鼻漏型鼻炎としては、例えば、味覚性鼻炎、冷気吸入性鼻炎および老人性鼻炎が挙げられる。
浮腫型鼻炎としては、例えば、アスピリン過敏性鼻炎が挙げられる。
さらに、本発明の外用剤は、ステロイド薬といった従来用いられてきた鼻炎治療剤によって治療困難な鼻炎に対しても症状の改善効果を示す。
また、本発明の外用剤は、上記環状ペプチドの効果を目的として、上述した以外の用途にも用いることができる。この場合において、本発明の外用剤は、上記環状ペプチドの効果以外の効果を主目的としてもよい。この場合、本発明の環状ペプチド、その誘導体および/または薬学的に許容可能な塩は、外用剤の主たる効果を補助するまたは主たる効果以外の効果を追加する目的で用いられる。
本発明の外用剤は、皮膚または粘膜の目的とする部位(例えば患部)に局所的に投与されることにより、有効成分たる環状ペプチド、その誘導体および/または薬学的に許容可能な塩の効果を適用部位付近においてより確実かつ迅速に発現させることができる。
このような外用剤は、特に限定されないが、例えば、外皮用剤、点眼剤、点耳剤、点鼻剤、口腔剤、または坐剤であることができる。これらのうち、本発明の外用剤が、皮膚炎治療剤、皮膚炎予防剤、鎮痒剤、スキンケア用品、脱毛症治療剤、脱毛症予防剤、育毛剤または発毛剤である場合には、外皮用剤であることが好ましい。一方で、本発明の外用剤が鼻炎治療剤および/または鼻炎予防剤である場合、点鼻剤であることが好ましい。さらに角膜疾患治療および/予防剤である場合、点眼剤であることが好ましい。
外用液剤は、皮膚等に対し塗布するための液状の製剤である。このような外用液剤としては、例えばローション剤およびリニメント剤が挙げられる。
軟膏剤は、皮膚に塗布する、有効成分を基剤に溶解または分散させた半固形の製剤である。また、軟膏剤は、唇等の局所に塗布するためのリップクリームであってもよい。
クリーム剤は、皮膚に塗布する、水中油型または油中水型に乳化した半固形の製剤である。
貼付剤は、皮膚に貼付する製剤である。貼付剤としては、例えばテープ剤およびパップ剤が挙げられる。
点鼻剤は、鼻腔または鼻粘膜に投与する製剤である。点鼻剤としては、例えば、点鼻粉末剤および点鼻液剤が挙げられる。このうち、点鼻液剤が好ましい。
無機化合物のゲル化剤としては、例えば、含水性又は吸水性のケイ酸塩、例えばケイ酸アルミニウム(例えばベントナイト)、ケイ酸マグネシウム-アルミニウム、コロイドシリカ等が挙げられる。
有機化合物のゲル化剤としては、天然、半合成又は合成のポリマーの使用が可能である。天然および半合成ポリマーとしては、例えば、セルロース等の多糖類、デンプン、トラガカント、アラビアゴム、キサンタンガム、寒天、ゼラチン、アルギン酸及びその塩(例えばアルギン酸ナトリウム及びその誘導体)、低級アルキルセルロース(例えばメチルセルロース又はエチルセルロース)、カルボキシ-又はヒドロキシ-低級-アルキルセルロース(例えばカルボキシメチルセルロース又はヒドロキシプロピルセルロース)等が挙げられる。合成ポリマーとしては、例えば、カルボキシルビニルポリマー、ポリアクリル酸ナトリウム、(ビニルメチルエーテル/マレイン酸エチル)コポリマー、ポリメタクリレート、ポリビニルアルコール、ポリビニルピロリドン、ポリアクリル酸又はポリメタクリル酸等が挙げられる。なお、ゲル剤として、例えば、ルブラジェルNP、ルブラジェルCG、ルブラジェルDV、ルブラジェルMS、ルブラジェルOIL、ルブラジェルTW、ルブラジェルDS等(アシュランド社)等の市販のゲル化剤を用いることもできる。
フッ素系の油相成分としては、例えば、パーフルオロポリエーテル、フッ素変性オルガノポリシロキサン、フッ化ピッチ、フルオロカーボン、フルオロアルコール、フルオロアルキル・ポリオキシアルキレン共変性オルガノポリシロキサン等が挙げられる。
アニオン性界面活性剤としては、例えば、脂肪酸セッケン、α-アシルスルホン酸塩、アルキルスルホン酸塩、アルキルアリルスルホン酸塩、アルキルナフタレンスルホン酸塩、アルキル硫酸塩、POEアルキルエーテル硫酸塩、アルキルアミド硫酸塩、アルキルリン酸塩、POEアルキルリン酸塩、アルキルアミドリン酸塩、アルキロイルアルキルタウリン塩、N-アシルアミノ酸塩、POEアルキルエーテルカルボン酸塩、アルキルスルホコハク酸塩、アルキルスルホ酢酸ナトリウム、アシルイセチオン酸塩、アシル化加水分解コラーゲンペプチド塩、パーフルオロアルキルリン酸エステル等が挙げられる。
ノニオン性界面活性剤としては、例えば、プロピレングリコール脂肪酸エステル、グリセリン脂肪酸エステル、ポリグリセリン脂肪酸エステル、ソルビタン脂肪酸エステル、POEソルビタン脂肪酸エステル、POEソルビット脂肪酸エステル、POEグリセリン脂肪酸エステル、POEアルキルエーテル、POE脂肪酸エステル、POE硬化ヒマシ油、POEヒマシ油、POE・POP共重合体、POE・POPアルキルエーテル、ポリエーテル変性シリコーンラウリン酸アルカノールアミド、アルキルアミンオキシド、水素添加大豆リン脂質、水酸化大豆リン脂質、高分子系界面活性剤、バイオサーファクタント等が挙げられる。
なお、天然系界面活性剤も用いることができ、このような界面活性剤としては、例えば、レシチン、サポニン、糖系界面活性剤等が挙げられる。
次に、本発明の外用剤の使用方法について説明する。
本発明の外用剤の使用方法は、上述した本発明の外用剤を、対象の皮膚および/または粘膜に適用することを含む。
本発明の外用剤のより具体的な使用方法は、以下のとおりである。
本発明の外用剤を、皮膚炎治療剤または皮膚炎予防剤として用いる場合、当該外用剤を目的とする皮膚および/または粘膜部位(例えば皮膚炎が発症した患部)に対し直接適用することができる。
本発明の外用剤を、鎮痒剤として用いる場合、当該外用剤を目的とする皮膚および/または粘膜部位に対し直接適用することができる。
適用頻度としては、特に限定されないが、例えば、1~10回/日、好ましくは1~5回/日、さらに好ましくは1~3回/日である。
また、用量としては特に限定されないが、例えば、適用1回につき、本発明の環状ペプチドおよびその誘導体ならびにこれらの薬学的に許容可能な塩の合計量を0.0001~1000000μg/mL、好ましくは0.001~10000μg/mL、より好ましくは0.01~1000μg/mL、さらに好ましくは0.1~100μg/mL、特に好ましくは1~100μg/mLとすることができる。また、別の態様において、0.1~800μg/mL、1~500μg/mLの濃度で含んでよい。
本発明の外用剤を、化粧料として用いる場合、当該外用剤を目的とする皮膚および/または粘膜部位に対し直接適用することができる。 適用頻度としては、特に限定されないが、例えば、1~10回/日、好ましくは1~5回/日、さらに好ましくは1~3回/日である。
また、用量としては特に限定されないが、例えば、適用1回につき、本発明の環状ペプチドおよびその誘導体ならびにこれらの薬学的に許容可能な塩の合計量を0.0001~1000000μg/mL、好ましくは0.001~10000μg/mL、より好ましくは0.01~1000μg/mL、さらに好ましくは0.1~100μg/mL、特に好ましくは1~100μg/mLとすることができる。また、別の態様において、0.1~800μg/mL、1~500μg/mLの濃度で含んでよい。
本発明の外用剤を、脱毛症治療剤、脱毛症予防剤、発毛剤または育毛剤ならびに/または抜け毛防止法として用いる場合、当該外用剤を目的とする部位(例えば、頭皮、皮膚の脱毛部位)に対し直接適用することができる。
また、用量としては特に限定されないが、例えば、適用1回につき、本発明の環状ペプチドおよびその誘導体ならびにこれらの薬学的に許容可能な塩の合計量を0.0001~1000000μg/mL、好ましくは0.001~10000μg/mL、より好ましくは0.01~1000μg/mL、さらに好ましくは0.1~100μg/mL、特に好ましくは1~100μg/mLとすることができる。また、別の態様において、0.1~800μg/mL、1~500μg/mLの濃度で含んでよい。
本発明の外用剤を、鼻炎治療剤または鼻炎予防剤として用いる場合、当該外用剤を目的とする部位(例えば、鼻腔粘膜)に対し直接適用することができる。適用頻度としては、特に限定されないが、例えば、1~10回/日、好ましくは1~5回/日、さらに好ましくは1~3回/日である。
また、用量としては特に限定されないが、例えば、適用1回各鼻腔につき、本発明の環状ペプチドおよびその誘導体ならびにこれらの薬学的に許容可能な塩の合計量を好ましくは0.001~10000μg/mL、より好ましくは0.01~1000μg/mL、さらに好ましくは0.1~100μg/mL、特に好ましくは1~100μg/mLとすることができる。また、別の態様において、0.1~800μg/mL、1~500μg/mLの濃度で含んでよい。
次に、本発明の医薬について説明する。
本発明の医薬は、1種以上の本発明の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩を含む。
本発明の医薬が適用可能な疾患としては、特に限定されないが、例えば、上述した各種疾患の他、高血圧症、不安定狭心症、急性心筋梗塞、浮腫性疾患、腎不全、心不全、免疫疾患、肥満、メタボリックシンドローム等が挙げられる。
まず、式Iで表されるアミノ酸配列からなる環状ペプチドを合成した。
具体的には、ペプチド合成機を用いて、ペプチド固相合成法により、アミノ酸を順次結合して17個のアミノ酸からなる直鎖状のペプチドを形成した。その後、N末端から数えて1番目のCysおよび17番目のCysにある保護基を脱離させた。その後、ヨウ素(I2)処理を行って、酸化的に同アミノ酸残基間のシステイン結合を形成し、環状ペプチドを形成した。
得られ環状ペプチドを含む組成物について、逆相液体高速クロマトグラフィー(逆相HPLC)による精製を行い、その後凍結乾燥を行って、白色粉末としての環状ペプチドの精製物を得た。
HPLCの条件を以下に示す。
装置:Agilent 1100
流速:1.0ml/min
溶離液A:0.1%トリフルオロ酢酸/水
溶離液B:0.1%トリフルオロ酢酸/アセトニトリル
勾配:80%溶離液B アイソクラティック
質量分析(MS)の条件を以下に示す。
装置:Thermo Finnigan LCQ Advantage
イオン化法:エレクトロスプレーイオン化
分析法:イオントラップ法
カラム:Discovery C18、4.6mm×250mm、粒径5ミクロン
カラム温度:室温
溶離液A:0.1%トリフルオロ酢酸/水
溶離液B:0.1%トリフルオロ酢酸/アセトニトリル
勾配:20~40%溶離液B/20分
流量:1.2ml/分
温度:室温
注入量:20μl
検出器:UV検出器(検出波長215nm)
測定の結果、得られたタンパク質の純度は、99.2%であることが確認された。
2.1 ゲル製剤の製造
式Iで表されるアミノ酸配列からなる環状ペプチド(以下の実施例において「C環」という場合、式Iで表される環状ペプチドを意味する)を含むゲルベース製剤(C環ゲル製剤、実施例)およびヒトCNPを含むゲルベース製剤(CNPゲル製剤、比較例)を以下のようにして製造した。
パラオキシ安息香酸メチルエステル(商品名:メッキンスM、上野製薬製)0.1g、フェノキシエタノール0.2g、1,2-ペンタンジオール3.0gを同一容器中に秤量し、60~70℃に加熱して均一な溶液とし、混合釜に投入した。
次に、混合釜に、濃グリセリン6.0gを投入し、その後、カルボキシビニルポリマー(商品名:カーボポール940、ルーブリゾール・アドバンスト・マテリアルズ社製)0.44gとキサンタンガム(商品名:ケルトロールT、CP KELCO社製)0.08gの混合物を加えてパドルで撹拌し、これらを十分に分散させた。
次に、ヒトCNP-22:1mg(American Peptide Company社)を、1mLの精製水に溶解して得られたCNP溶液22μlを上記で得られたゲルベース10gに均一に撹拌混合してCNP-22の濃度が約1μMのゲルベース製剤(CNPゲル製剤)を製造した。同様にして、CNP-22の濃度が約2.0μM、5.0μMのゲルベース製剤を製造した。なお、以下の実施例において、特に記載しない限り、「CNPゲル製剤」は、約1μMのCNP濃度のものを使用した。
式IIで表されるアミノ酸配列からなる環状ペプチド(C環)を含む点鼻剤(C環点鼻剤、実施例)およびヒトCNPを含む点鼻剤(CNP点鼻剤、比較例)を以下のようにして製造した。
次に、C環点鼻液を、定量式の点鼻用噴霧容器(アズワン株式会社製)に充填し、さらに1回あたりの噴霧量を100μl(0.1ml)となるように調節して、C環点鼻剤を得た。
3.1 C環ゲル製剤の効果確認
種々の皮膚炎に罹患した被験者について、前記のC環ゲル製剤を患部に塗布し、塗布前後の症状の変化を観察した。なお、可能な場合、比較例として同一の被験者に対し、C環ゲル製剤を塗布していない患部に前記のCNPゲル製剤を塗布し、塗布前後の症状の変化を観察した。なお、掻痒感については、患部毎にVAS(Visual analogue scale)を用いて10段階で評価した。
試験結果を、被験者の年齢、性別、症状および被験者に対する処方とともに以下の表に示す。
特に、C環ゲル製剤を適用した場合には、適用直後から掻痒感の軽快、消失が観察された。皮膚炎においては、一般に、患者は掻痒感を覚えると、掻痒感を覚えた部位を掻きむしる傾向にあり、これが皮膚炎の重症化の一因となり得る。しかしながら、このように掻痒感が顕著に軽快、消失することにより、結果的に皮膚炎の重症化を防止することが可能となる。
種々の皮膚炎に罹患した被験者について、C環ゲル製剤およびゲルベースを患部に塗布し、塗布前後の症状の変化を観察した。これらの効果を以下の表にまとめた。
以下に乾癬の症例についての治療効果についてまとめた。上記同様に、C環ゲル製剤を乾癬の患部に塗布し、塗布前後の症状の変化を観察した。なお、可能な場合、比較例として同一の被験者に対し、C環ゲル製剤を塗布していない患部に前記のCNPゲル製剤を塗布し、塗布前後の症状の変化を観察した。 試験結果を、被験者の年齢、性別、症状および被験者に対する処方とともに下の表に示す。
C環を含む化粧料による効果は、C環を含んだゲル剤、入浴剤および頭髪化粧品(シャンプー、リンス)またはボディーソープとして使用した結果を評価し、その効果を確認した。
4.1.1 肌質改善効果の確認(C環ゲル製剤とCNPゲル製剤との比較)
被験者に対し、上記のC環ゲル製剤、CNPゲル製剤を処方した。そして、各被験者の頬や目元に、C環ゲル製剤を右側に、CNPゲル製剤を左側に塗布して、肌状態の変化を観察し比較した。またその症例と評価を以下の表にまとめた。なお、肌状態の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
さらに、40歳代~60歳代の被験者では、C環ゲル製剤塗布後迅速に、たるみ、シワ、乾燥が改善され、肌が引きしまり、くすみ、シミ、たるみ、くまが目立たなくなるなどという効果が顕著に見られ、その効果はCNPゲル剤塗布した際の効果より大きかった。
C環ゲル製剤とCNPゲル製剤の効果におけるゲルベースの寄与の有無を検討するために、1名の被験者の右顔面にC環ゲル製剤を、左顔面にゲルベースを塗布し、被験者の顔面の肌状態の変化について観察した。
唇荒れの症状を有する正常被験者に対し、C環ゲル製剤を塗布し、唇の粘膜の状態の変化を観察し、以下の表にまとめた。なお、粘膜の状態の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
頭皮・毛髪の症状を有する正常被験者に対し、C環ゲル製剤を塗布し、頭皮および毛髪の状態の変化を観察し、以下の表にまとめた。なお、頭髪・毛髪の状態の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
C環を0.01μMになるように溶解した37~41℃のお湯(お湯200Lに対してC環20μM溶液を100ml溶解)に、1回/日、14日間、被験者を入浴させ、被験者の皮膚状態をさら湯(お湯のみ)のときと比較した。またその症例と評価を以下の表にまとめた。なお、皮膚状態の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
C環ゲル製剤、CNPゲル製剤を塗布し、種々の脱毛に関する症状に対する効果を観察した。またその症例と評価を以下の表にまとめた。なお、症状の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
C環ゲル製剤、CNPゲル製剤を塗布し、AGAにおける症状に対する効果を観察した。またその症例と評価を以下の表にまとめた。なお、症状の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
上記の女性型脱毛症、男性型脱毛症、汎発性脱毛症、蛇行状脱毛症、多発性脱毛症を有する被験者の症例においても、実施例に係るC環ゲル製剤を適用した場合、抜け毛が顕著に減少し、硬毛の発毛範囲が拡大し、その成長も早かった。さらに、既存の毛髪のハリが生じ、そのコシが強くなった。いずれも比較例にかかるCNPゲル製剤を適用した場合と比較して、その症状の改善が顕著に表れた。すなわち、Cゲル製剤は、CNPゲル製剤と比較して、上記症状に対する効能が優れていた。
さらに、C環ゲル製剤は、脂漏性を改善し、頭皮を清浄にし、フケを抑えることができた。また、白髪を予防し、黒い毛を生やし、薄毛の改善をもたらすものであった。さらには、かゆみを抑える効果は10分後には抑えることができ、その即効性の効果が高いことがわかった。
6.1 症例
C環点鼻剤、CNPゲル点鼻剤を噴霧し、被験者の鼻炎等に対する効果を観察した。またその症例と評価を以下の表にまとめた。なお、症状の変化は、被験者の体感的な評価と、医師としての本発明者による客観的な観察とに基づいて判定した。
上記いずれの症例においても、実施例に係るC環点鼻剤を適用した場合、鼻漏、鼻閉ともに比較例にかかるCNP点鼻剤を適用した場合と比較して、その改善、解消が迅速に行われていた。すなわち、C環点鼻剤は、CNP点鼻剤と比較して即効性に優れていた。また、C環点鼻剤の効能はCNP点鼻点鼻剤の効能と比較して同等以上であり、また、その効能の持続時間が長く、症状の再発を抑える事ができるものであった。
本発明のC環化合物が従来のCNPに比べて各疾病等に対する薬理効果に優れることについては、以上のとおり、各臨床例に基づきデータをもって説明したが、かかる薬理効果は発明者らが行った、化合物の立体構造解析の結果からも裏付けられるものであることについて参考のため以下の実験レポートをもって説明する。
ヒトCNP(CNP-22)と、同CNPの受容体であるB型受容体(NPR-B)との結合状態を検討するため、立体構造を用いた、ホモロジーモデリングによるin silico解析を行った。モデリングには、Swiss-Pdb viewerおよびSWISS-MODELを使用した。
まず、上記解析に先立ち、ヒトCNPとB型受容体との間の結合状態の検討のためのテンプレート構造を選定した。このテンプレート構造として、ラットNPR-AとラットANPペプチドとの複合体の立体構造(PDB ID:1T34)を使用した。ラットNPR-Aは、A鎖、B鎖からなるホモ二量体である。そして、このようなラットNPR-Aは、ラットANPのCys7~Arg27の21残基が結合した状態でX線結晶構造解析により立体構造が決定されている。また、ラットNPR-Aの立体構造は、タンパク質立体構造データベースであるProtein Data Bankから入手した。また、ヒトNPR-BとラットNPR-Aのアミノ酸一致度は45%である。
今回、CNPのペプチドモデルとして、ヒトCNP(CNP-22)のCys6~Cys22の領域のアミノ酸配列である、Cys-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Gly-Ser-Met-Ser-Gly-Leu-Gly-Cys(配列番号:5)を使用した。なお、当然ながら、当該CNPペプチドモデルの領域は本発明のC環と一致する。
ヒトNPR-BのヒトCNP結合に関与するアミノ酸残基を推察するため、CNPペプチドがヒトNPR-Bに結合した複合体モデルをホモロジーモデリングにより構築した。具体的には、ホモロジーモデリングにより、テンプレート構造のラットANPペプチドに基づいてヒトCNPペプチドモデルを、テンプレート構造のラットNPR-Aに基づいてヒトNPR-Bのモデル構造をモデリングした。
次に、ヒトCNPペプチドモデルとヒトNPR-Bとの間で検出されたアミノ酸残基から、相互作用に直接関与する残基を推測した。
構築した複合体モデルでは、CNPペプチドモデルとNPR-BのA鎖との間に、Phe2およびLeu4の側鎖による疎水性結合、Cys1の主鎖、Lys5およびArg8の側鎖による水素結合が推測された。また、CNPペプチドモデルとNPR-BのB鎖との間には、Met12の側鎖による疎水性結合、Gly16の主鎖、Arg8の側鎖による水素結合が推測された。なお、CNPペプチドモデルのCys1、Phe2、Leu4、Lys5、Arg8、Met12、Gly16は、それぞれ、ヒトCNP(CNP-22)のCys6、Phe7、Leu9、Lys10、Arg13、Met17、Gly21に対応する。ヒトCNPのうち、これらのアミノ酸残基が、NPR-Bの活性化に寄与する残基であると考えられる。
以上より、in silico解析による立体構造解析から、ヒトCNPのNPR-B活性化に寄与する残基は、その環状部分、すなわちC環に存在することが推測された。
構築した複合体のモデル構造を使用して、相互作用が推察されたアミノ酸残基以外のアミノ酸残基の置換可能性について検討を行った。
具体的には、相互作用が推察されたアミノ酸残基以外のアミノ酸残基を他のアミノ酸に置換した際に、置換ペプチドが、NPR-Bに対して結合可能か否かを検討するために、CNPの変異体モデルを作製し、相互作用について解析した。モデリングには、Swiss-Pdb viewerを使用した。
・NPR-Bに結合する際に立体障害を起こさない。NPR-BとCNP変異体モデル構造において、原子間の衝突が見られない。
・表面の静電ポテンシャルに影響を与えない。
・分子内エネルギーの値が大きく増加しない(原子間の結合に無理な角度やねじれを生じない)。
・NPR-BとCNPとの鎖間およびCNPの鎖内で本来見られない水素結合を形成しない。
・Cavity(空洞、すき間)を生じない。
次に、一部のアミノ酸を置換した環状ペプチドについて、その効果を確認すべく以下の試験に供した。なお、上記環状ペプチドの製造方法および製造されたペプチドのアミノ酸配列の確認方法は、上記した環状ペプチドの製造方法および質量分析方法と同様であった。なお、試験に用いた環状ペプチドの変異体などは下表の環状ペプチドを用いた。また、下表は、本発明の環状ペプチドの一例であり、これらに限定されるものではない。下表おいて、変異させる数で例えば「0~2」との記載は、配列中、任意に0、1、2個のアミノ酸を変異させてもよいことを示す。なお、配列番号22~31、42~47、54~56、60~62の場合において、いずれの場合においても、配列番号3(すなわち、アミノ酸変異が0)の場合を除くこともできる。
得られた環状ペプチドを、精製水で1、5、30、100、500μg/mlに配合し患部に塗布した。なお、表中の処方A~Eは、それぞれ1、5、30、100、500μg/mlの環状ペプチド濃度を指す。なお、ペプチドを配合しない、精製水で処置した場合は、効果がないことから、プラセボ効果ではないことが確認された。
上記結果より、本発明の環状ペプチドの一部のアミノ酸を置換した環状ペプチドであっても、式IIで表される環状ペプチド(配列番号3)と同等以上の効果を奏することが実証された。また、置換した環状ペプチドを混合して適用した場合においても、有効量の環状ペプチドを適用することで、同様の効果を得ることができた。
特に、アトピー性皮膚炎、湿疹などを有する被験者に、1μg/ml~500μg/mlを患部に1回の単純塗布直後から、痒みを消失する、紅斑、浸潤、丘疹、掻き傷が上皮化、浸出液が止まる、亀裂が上皮化する等の即効性がみられた。また、わずか1回の塗布で、1週間以上その効果が続く持続性がみられた。なお、健常肌や肌荒れに適用した場合、塗布直後から数分以内に保湿効果を発揮して乾燥を改善し、皮膚および粘膜に適度な弾力性と柔軟性が付与・保持され、肌が柔らかくなり、皮膚、粘膜にハリが生じ、ひきしまる。また、適用部位において小じわややたるみが改善され、さらにくすみ、しみが目立たないものとなる。さらに光線過敏症、光線皮膚症を予防し、光線による炎症症状が起きない、または起きにくくなる効果がある。これらは、1回の塗布で1週間以上の効果の持続性がみられた。
得られた環状ペプチドを、精製水で1、5、30、100、500μg/mlに配合し患部に塗布した。なお、表中の処方A~Eは、それぞれ1、5、30、100、500μg/mlの環状ペプチド濃度を指す。なお、ペプチドを配合しない、精製水で処置した場合は、効果がないことから、プラセボ効果ではないことが確認された。
得られた環状ペプチドを、精製水で1、5、30、100、500μg/mlに配合し患部に塗布した。なお、表中の処方A~Eは、それぞれ1、5、30、100、500μg/mlの環状ペプチド濃度を指す。なお、ペプチドを配合しない、精製水で処置した場合は、効果がないことから、プラセボ効果ではないことが確認された。
1μg/ml~500μg/ml、0.1mlを各鼻腔、患部に1回点鼻した直後から鼻汁を止め、鼻閉を改善し、鼻腔粘膜の痒みやくしゃみを止める即効性と、わずか1回の点鼻塗布で、1日持続し、症例によっては1週間以上その効果が続く持続性がみられた。CNP投与と比較すると、治療効果が高いだけでなく、即効性があり、さらに非常に低濃度で作用する効果があった。
本発明は、従来のステロイド薬といった従来用いられてきた鼻炎治療剤によって、局所刺激が強く、点鼻薬使用を希望されない被験者でも、全く局所刺激がないので、安心して使うことができる。
Claims (28)
- 配列番号60~62から選択される、請求項1に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
- 配列番号22~31、42~47および54~56から選択される、請求項1に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
- 配列番号6~21、32~41、48~53および57~59から選択される、請求項1に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
- 誘導体が環状ペプチド中の水素原子、水酸基、カルボキシ基、アミノ基、イミノ基に対して置換可能な置換基で置換されたものである、請求項1~4のいずれか一項に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩。
- 請求項4に記載の環状ペプチド中のアミノ酸の1以上6以下を欠失させるか、他のアミノ酸で置換または付加することにより形成され、かつ前記各式で表される環状ペプチドと同等の機能を有する環状ペプチドもしくはその誘導体またはその薬学的に許容可能な塩。
- 請求項1~6のいずれか一項に記載の環状ペプチドおよび/もしくはその誘導体ならびに/またはこれらの薬学的に許容可能な塩を1種以上含む、外用剤。
- 皮膚炎治療剤、皮膚炎予防剤、鎮痒剤、消炎剤、表皮再生促進剤またはスキンケア用品の材料である、請求項7に記載の外用剤。
- スキンケア用品が、保湿用および/または肌荒れ防止・改善用および/または敏感肌防止・改善用および/または乾燥肌防止・改善用および/または皮脂改善・ニキビケア用および/または刺激緩和・抗炎症用および/または美白用および/または老化防止用および/またはシワ・たるみおよび/またはくすみ・くま防止・改善用および/または光線過敏症防止・改善用および/または紫外線傷害予防・緩和用および/またはスリミング用および/または皮膚清浄用である、請求項8に記載の外用剤。
- 入浴剤、身体洗浄剤、頭髪用洗浄剤、リンス・トリートメント、トニック、ヘヤオイル、ヘアローション、スカルプケア剤である、請求項8に記載の外用剤。
- 脱毛症治療剤、脱毛症予防剤、育毛剤および/または発毛剤および/または抜け毛予防剤・防止剤、抜け毛予防化粧料、である、請求項7に記載の外用剤。
- フケやかゆみの予防・改善用および/または毛髪、頭皮の乾燥改善・予防用および/または頭皮の脂漏性の改善・予防用のスカルプケア剤である、請求項7に記載の外用剤。
- 鼻炎治療剤および/または鼻炎予防剤および/または副鼻腔炎治療剤および/または副鼻腔炎予防剤である、請求項7に記載の外用剤。
- 化粧料である、請求項7に記載の外用剤。
- 剤形が、固形剤、半固形剤、粉末剤、液剤、スプレー剤、軟膏剤、クリーム剤、乳液剤、ゲル剤または貼付剤である、請求項7~14のいずれか一項に記載の外用剤。
- 請求項1~5のいずれか一項に記載の環状ペプチド/およびもしくはその誘導体ならびに/またはこれらの薬学的に許容な塩を0.0001~1000000μg/mLの濃度で含む、請求項7~15のいずれか一項に記載の外用剤。
- 医薬品、医薬部外品または化粧品として用いられる、請求項7~16のいずれか一項に記載の外用剤。
- 請求項1~5のいずれか一項に記載の環状ペプチドおよび/もしくはその誘導体ならびに/またはこれらの薬学的に許容可能な塩の外用剤の製造のための使用。
- 請求項7~17のいずれか一項に記載の外用剤を、対象の皮膚および/または粘膜に適用することを含む、外用剤の使用方法。
- 粘膜が口唇、口腔、鼻腔、眼または膣である、請求項18に記載の外用剤の使用方法。
- 皮膚炎の治療および/もしくは予防方法、痒みの軽減もしくは消失方法、びらん、潰瘍の治療方法またはスキンケア方法である、請求項18に記載の外用剤の使用方法。
- 湿疹、アトピー性皮膚炎、接触性皮膚炎、光線過敏症、乾癬、ざ瘡、嚢胞性ざ瘡、脂漏性湿疹、および痒みからなる群から選択される皮膚炎の治療および/または予防方法である、請求項18に記載の外用剤の使用方法。
- 肌荒れ、敏感肌、乾燥肌、脂性肌、光線過敏症、しわ、たるみ、くすみ、ふけおよび痒みの改善、および予防方法である、請求項18に記載の外用剤の使用方法。
- 薄毛、脱毛症の治療および/もしくは予防方法ならびに/または発毛方法ならびに/または育毛方法、抜け毛防止および/もしくは予防方法である、請求項18に記載の外用剤の使用方法。
- フケやかゆみの防止・予防方法、および/もしくは毛髪、頭皮の乾燥を改善・予防方法、および/もしくは頭皮の脂漏性の予防・改善方法である、請求項18に記載の外用剤の使用方法。
- 鼻炎、副鼻腔炎の治療および/または予防方法である、請求項18に記載の外用剤の使用方法。
- 請求項1~5のいずれか一項に記載の環状ペプチドもしくはその誘導体またはこれらの薬学的に許容可能な塩を1種以上含む、医薬。
- 高血圧症、不安定狭心症、急性心筋梗塞、浮腫性疾患、腎不全、心不全、免疫疾患、自己免疫疾患、アレルギー疾患、癌、消化器系疾患、クローン病 、潰瘍性大腸炎、肥満、メタボリックシンドロームの治療薬である、請求項27に記載の医薬。
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US (1) | US20190119325A1 (ja) |
EP (2) | EP3689897A1 (ja) |
JP (2) | JP7253220B2 (ja) |
KR (1) | KR20180029255A (ja) |
CN (1) | CN109348717A (ja) |
AU (1) | AU2016302644A1 (ja) |
CA (1) | CA2994091A1 (ja) |
TW (1) | TW201717990A (ja) |
WO (1) | WO2017022728A1 (ja) |
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KR102094220B1 (ko) * | 2018-11-21 | 2020-03-30 | 주식회사 에스스킨 | 사이클릭 트리펩타이드, 이의 제조 방법, 및 이를 포함하는 피부 미백용 조성물 |
CN117462440A (zh) * | 2023-12-26 | 2024-01-30 | 杭州湃肽生化科技有限公司 | 功能性环肽及其制备方法及应用 |
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WO2002074234A2 (en) * | 2001-03-20 | 2002-09-26 | Prochon Biotech Ltd. | Method and composition for treatment of skeletal dysplasias |
WO2010078325A2 (en) * | 2008-12-29 | 2010-07-08 | Mayo Foundation For Medical Education And Research | Natriuretic polypeptides for reducing or preventing restenosis |
WO2010135541A2 (en) * | 2009-05-20 | 2010-11-25 | Biomarin Pharmaceutical Inc. | Variants of c-type natriuretic peptide |
WO2011010732A1 (ja) * | 2009-07-23 | 2011-01-27 | 株式会社 イギス | 皮膚外用剤組成物 |
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JP2977158B2 (ja) * | 1990-09-07 | 1999-11-10 | 壽之 松尾 | トリ由来新規生理活性ペプチド(ニワトリcnp) |
KR20070007842A (ko) * | 2004-03-31 | 2007-01-16 | 카즈와 나카오 | 신장증가용 조성물 |
KR101207155B1 (ko) * | 2004-03-31 | 2012-12-04 | 카즈와 나카오 | 관절염증 치료제 또는 예방제 |
EP2217620A2 (en) * | 2007-11-21 | 2010-08-18 | BioMarin Pharmaceutical Inc. | Variants of c-type natriuretic peptide |
US8150603B2 (en) | 2008-11-26 | 2012-04-03 | Caterpillar Inc. | Engine control system having fuel-based timing |
ITPG20090061A1 (it) | 2009-11-27 | 2011-05-28 | Andrea Marcantonini | Impianto mobile per la produzione di calcestruzzo |
-
2016
- 2016-08-01 TW TW105124367A patent/TW201717990A/zh unknown
- 2016-08-01 JP JP2017533067A patent/JP7253220B2/ja active Active
- 2016-08-01 AU AU2016302644A patent/AU2016302644A1/en not_active Abandoned
- 2016-08-01 EP EP19214498.8A patent/EP3689897A1/en active Pending
- 2016-08-01 US US15/749,275 patent/US20190119325A1/en not_active Abandoned
- 2016-08-01 CA CA2994091A patent/CA2994091A1/en active Pending
- 2016-08-01 CN CN201680044609.6A patent/CN109348717A/zh active Pending
- 2016-08-01 KR KR1020187005576A patent/KR20180029255A/ko not_active Application Discontinuation
- 2016-08-01 WO PCT/JP2016/072562 patent/WO2017022728A1/ja active Search and Examination
- 2016-08-01 EP EP16833007.4A patent/EP3330280A4/en not_active Withdrawn
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2022
- 2022-10-24 JP JP2022169775A patent/JP2022183376A/ja active Pending
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US5434133A (en) * | 1991-01-31 | 1995-07-18 | Suntory Limited | CNP analog peptides and their use |
WO2002074234A2 (en) * | 2001-03-20 | 2002-09-26 | Prochon Biotech Ltd. | Method and composition for treatment of skeletal dysplasias |
WO2010078325A2 (en) * | 2008-12-29 | 2010-07-08 | Mayo Foundation For Medical Education And Research | Natriuretic polypeptides for reducing or preventing restenosis |
WO2010135541A2 (en) * | 2009-05-20 | 2010-11-25 | Biomarin Pharmaceutical Inc. | Variants of c-type natriuretic peptide |
WO2011010732A1 (ja) * | 2009-07-23 | 2011-01-27 | 株式会社 イギス | 皮膚外用剤組成物 |
WO2011024973A1 (ja) * | 2009-08-27 | 2011-03-03 | 株式会社 イギス | 鼻炎治療剤 |
WO2012099258A1 (ja) * | 2011-01-21 | 2012-07-26 | 株式会社 イギス | 脱毛症治療剤 |
Also Published As
Publication number | Publication date |
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JPWO2017022728A1 (ja) | 2018-06-21 |
KR20180029255A (ko) | 2018-03-20 |
JP2022183376A (ja) | 2022-12-08 |
EP3330280A1 (en) | 2018-06-06 |
TW201717990A (zh) | 2017-06-01 |
JP7253220B2 (ja) | 2023-04-06 |
EP3330280A4 (en) | 2019-06-12 |
EP3689897A1 (en) | 2020-08-05 |
US20190119325A1 (en) | 2019-04-25 |
AU2016302644A1 (en) | 2018-03-08 |
CN109348717A (zh) | 2019-02-15 |
CA2994091A1 (en) | 2017-02-09 |
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