WO1995023580A1 - Preventive and remedy for secondary depilation - Google Patents

Preventive and remedy for secondary depilation Download PDF

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Publication number
WO1995023580A1
WO1995023580A1 PCT/JP1995/000350 JP9500350W WO9523580A1 WO 1995023580 A1 WO1995023580 A1 WO 1995023580A1 JP 9500350 W JP9500350 W JP 9500350W WO 9523580 A1 WO9523580 A1 WO 9523580A1
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hair loss
administration
group
hair
copper
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PCT/JP1995/000350
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French (fr)
Japanese (ja)
Inventor
Katsumi Nogimori
Akio Terashima
Mikako Ohashi
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Procyte Corporation
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Priority to AU18614/95A priority Critical patent/AU1861495A/en
Publication of WO1995023580A1 publication Critical patent/WO1995023580A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/58—Metal complex; Coordination compounds

Definitions

  • the present invention relates to an agent for preventing and treating secondary hair loss characterized by containing a tripeptide monocopper complex having an excellent effect in preventing and treating secondary hair loss induced by administration of an anticancer agent or the like.
  • An object of the present invention is to prevent and treat secondary hair loss, which is a side effect of chemotherapy or radiation therapy such as administration of an anticancer drug, more reliably.
  • the “secondary hair loss” in the present invention means a hair loss symptom secondary to a side effect caused by chemotherapy such as administration of an anticancer agent or radiation therapy.
  • chemotherapy such as administration of an anticancer agent or radiation therapy.
  • peptide-copper complexes have a hair growth-promoting effect on male pattern baldness, in which men lose their hair with age, but it has still been demonstrated that they are effective in secondary hair loss. Did not.
  • the present inventors thought that the peptide-copper complex was effective in preventing and treating secondary hair loss, and made extensive studies using a rat chemotherapy hair loss model.
  • FIG. 1 is a diagram showing the degree of hair loss of the whole body of the test substance-administered group, control group (vehicle-administered group), and normal group (anti-cancer drug-non-administered group) in Example 1 as a hair loss score as a criterion. It is.
  • FIG. 2 is a diagram showing animals in a test substance administration group on day 13 after the start of anticancer drug administration in Example 1.
  • FIG. 3 is a diagram showing animals in a control group on day 13 after the start of anticancer drug administration in Example 1.
  • FIG. 4 is a diagram showing animals in a normal group on day 13 after the start of anticancer drug administration in Example 1.
  • FIG. 5 is a diagram showing the degree of hair loss in the whole body of the test substance-administered group, the control group (vehicle-administered group), and the normal group (anti-cancer drug-non-administered group) in Example 2 as a hair loss score as a criterion. It is.
  • FIG. 6 is a diagram showing animals in a test substance administration group on day 14 after the start of anticancer drug administration in Example 2.
  • FIG. 7 is a diagram showing animals in a control group on day 14 after the start of anticancer drug administration in Example 2.
  • FIG. 8 is a diagram showing animals in the normal group on day 14 after the start of anticancer drug administration in Example 2.
  • Figure 9 shows the test substance-applied group and the control group (vehicle) on day 21 after hair removal in Example 3.
  • Fig. 2 shows the degree of hair loss of the animals in the application group) as a percentage of the area of hair removal relative to the area of hair removal.
  • FIG. 10 is a diagram showing the animals in the normal group (the group not administered with an anticancer drug) 21 days after hair removal in Example 3.
  • FIG. 11 shows the animals in the test substance application group 21 days after hair removal in Example 3.
  • FIG. 12 is a diagram showing animals of a control group (vehicle-applied group) 21 days after hair removal in Example 3.
  • the active ingredient of the present invention is a triptide copper complex represented by the general formula X: copper (II) (wherein X represents a tripeptide), and the constituent amino acids of tribetide are glycine, alanine, /, 'Lin, leucine, isoleucine, serine, threonine, cystine, cystine, methine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, proline, hydroxyproline, etc.
  • These amino acids can be prepared by a method described in JP-A-5-505808 by appropriately combining these three amino acids.
  • the amino acid may be either L-form or D-form.
  • L-alanyl-L-histidyl-L-lysine copper (11)
  • glycyl-L-histidyl L-lysine copper (11)
  • L-lysyl-L-histidyl-daricin complexes such as copper (II).
  • L-alanyl-L-histidyl-L-lysine copper (11)
  • glycyl-L-histidyl-L-lysine copper ( ⁇ )
  • L-aralanyl-L-histidyl-L —Lysine copper (II).
  • “copper ( ⁇ )” means a divalent copper ion, and is a tripeptide-copper (II) Although the molar ratio of tripeptide: copper ( ⁇ ) in the complex can be changed as appropriate, it is particularly preferably 1: 1 to 2: 1.
  • Particularly preferred tripeptide-copper (II) complexes include, for example, L-alanyl-L-histidyl L-lysine: copper ( ⁇ ) (1: 1), daricyl-L-histidyl L-lysine: copper (II) ( 1: 1), etc., and these triptotide-copper complexes can be used alone or as a mixture of two or more.
  • the agent for preventing or treating secondary hair loss of the present invention can be provided as a pharmaceutical, a quasi-drug, or a cosmetic, and its dosage form can be an intradermal injection or an external preparation.
  • bases such as creams, lotions, emulsions, ointments and gels can be used. If necessary, various preservatives, fragrances, stabilizers, coloring agents, humectants, thickeners, etc. Additives can also be added.
  • the amount of the secondary hair loss preventing / treating agent of the present invention can be appropriately changed depending on the kind of the drug used in the chemotherapy, the degree of the symptom, the dosage form, etc., but is usually about 0.001 to 10% by weight, preferably. Is incorporated in the preparation in an amount of about 0.01 to 5% by weight.
  • the dosage of the agent for preventing and treating secondary hair loss of the present invention usually varies depending on the administration method and dosage form, but is in the range of 0.1 to 4 ml per day for adults. This daily dose is administered once or several times a day. The daily dose may be larger than the above, if necessary.
  • the site of administration is preferably on the scalp.
  • Example 1 The test results of Example 1 are shown in FIG.
  • the whole body of the test substance-administered group, control group, and normal group animals 13 days after the start of anticancer drug administration is shown in FIGS. 2, 3, and 4, respectively.
  • Intradermal administration of L-alanyl-L-histidine-L-lysine Copper (II) (1: 1) 0.05 ml of a physiological saline solution containing 0.25% to one place at the center of the back of 8-day-old SD rats I do. From the next day, once a day, intraperitoneally administer Ar a-C at a dose of 25 mgZkg. The determination of the hair loss preventing effect was made by scoring the hair loss status of the whole body and the test substance administration site in the same manner as in Example 1. In the control group, only physiological saline was used.
  • Test results> The test results of Example 2 are shown in FIG.
  • test substance administration group of the present invention In the 0.25% test substance administration group of the present invention, almost the whole body hair excluding the administration site showed a hair loss pattern similar to that of the control group, but hair loss was prevented around the test substance administration site, and scars due to intradermal administration were observed. Was also not recognized.
  • FIGS. 6, 7, and 8 The whole body images of the test substance administration group, control group, and normal group animals on day 14 after the start of anticancer drug administration are shown in FIGS. 6, 7, and 8, respectively.
  • Example 1 and Example 2 the effect of preventing intradermal administration of the substance of the present invention for hair loss due to chemotherapy was clarified. Whether or not the application of the substance of the present invention exerts a hair loss preventing effect was examined using a mouse chemotherapy hair loss model.
  • FIG. 9 shows the hair removal rate of the test substance-applied group and the control group (vehicle-applied group) on day 21 after hair removal as a percentage of the hair removal area to the hair removal area.
  • the whole body images of the normal group (anticancer drug-free group), the test substance-applied group, and the control group (vehicle-applied group) on day 21 after hair removal are shown in FIGS. 10, 11, and 12, respectively.
  • the agent for preventing and treating secondary hair loss of the present invention is effective for secondary hair loss.
  • the preventive / therapeutic agent for secondary hair loss of the present invention is useful as a preventive and therapeutic agent for secondary hair loss that exhibits an excellent effect.

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Abstract

A preventive and remedy for secondary depilation accompanying chemotherapy using carcinostatics or radiotherapy, which contains a tripeptide-copper complex represented by the general formula X:Cu(II), wherein X represents a tripeptide.

Description

明 細 書 二次性脱毛予防 ·治療剤 技術分野  Description Secondary hair loss prevention / therapeutic agent Technical field
本発明は、 抗癌剤などの投与により誘発される二次性脱毛の予防および治療に 卓越した効果を有するトリペプチド一銅錯体を含有することを特徴とする二次性 脱毛予防剤および治療剤に関する。 背景技術  The present invention relates to an agent for preventing and treating secondary hair loss characterized by containing a tripeptide monocopper complex having an excellent effect in preventing and treating secondary hair loss induced by administration of an anticancer agent or the like. Background art
癌化学療法の最近における進歩は目ざましく、 抗癌剤の開発や投与方法の工夫 などにより、 化学療法による癌患者の予後は著しく改善されている。 しかしなが ら、 抗癌剤のほとんどが通常の投与量で脱毛を引き起こすため、 患者の外観的ィ メージを損なうことによる精神的ショックは、 場合によっては患者の社会復帰を 願う意欲を損なうのみならず、 抗癌剤の投与そのものを拒否して効果的な治療が できなくなることすらある。  Recent advances in cancer chemotherapy have been remarkable, and the prognosis of cancer patients due to chemotherapy has been significantly improved due to the development of anticancer drugs and ingenious methods of administration. However, since most anticancer drugs cause hair loss at normal doses, mental shock by impairing the patient's appearance does not only impair the patient's willingness to reintegrate in some cases, In some cases, effective treatment cannot be achieved by refusing the administration of anticancer drugs.
抗癌剤投与による脱毛を防ぐ方法としては、 従来、 頭皮への血流を減少させ毛 嚢が薬剤に曝されないようにして脱毛を予防することを目的として、 頭皮締め付 け法、 頭皮冷却法などが考案されているが、 いずれも確実な方法ではない。 上述した従来の脱毛予防法は、 ある程度の脱毛予防効果が認められるものの、 患者の状態や薬剤の投与量、 投与方法、 併用薬剤の種類などに左右され、 その効 果は満足できるものではない。 発明の開示  Conventional methods of preventing hair loss due to administration of anticancer drugs include scalp tightening and scalp cooling, with the aim of reducing blood flow to the scalp and preventing hair follicles from being exposed to drugs to prevent hair loss. Although devised, none of these methods are reliable. Although the conventional hair loss prevention method described above has a certain degree of hair loss prevention effect, its effect is not satisfactory because it depends on the patient's condition, the dose of the drug, the administration method, and the type of concomitant drug. Disclosure of the invention
本発明は、 抗癌剤投与などの化学療法あるいは放射線療法の副作用である二次 性脱毛をより確実に予防および治療することを課題とするものである。  An object of the present invention is to prevent and treat secondary hair loss, which is a side effect of chemotherapy or radiation therapy such as administration of an anticancer drug, more reliably.
本発明における 「二次性脱毛」 とは、 抗癌剤投与などの化学療法あるいは放射 線療法などにより副作用として二次的に生じる脱毛症状を意味する。 従来、 ペプチド—銅錯体が、 男性が年齢とともに頭髮を失う男性型脱毛症に対 し発毛促進作用を有することが知られているが、 二次性脱毛に効果があることは いまだ実証されていなかった。 本発明者らは、 ペプチド—銅錯体が二次性脱毛の 予防および治療に効果があると考え、 ラッ卜の化学療法脱毛モデルを用いて、 鋭 意研究を重ねた。 The “secondary hair loss” in the present invention means a hair loss symptom secondary to a side effect caused by chemotherapy such as administration of an anticancer agent or radiation therapy. Conventionally, it has been known that peptide-copper complexes have a hair growth-promoting effect on male pattern baldness, in which men lose their hair with age, but it has still been demonstrated that they are effective in secondary hair loss. Did not. The present inventors thought that the peptide-copper complex was effective in preventing and treating secondary hair loss, and made extensive studies using a rat chemotherapy hair loss model.
その結果、 トリぺプチドー銅錯体が抗癌剤投与時の脱毛予防に卓越した効果を 有することを見いだし、 本発明を完成した。 図面の簡単な説明  As a result, they have found that the triptide-doped copper complex has an excellent effect in preventing hair loss during administration of an anticancer drug, and have completed the present invention. BRIEF DESCRIPTION OF THE FIGURES
図 1は実施例 1における被験物質投与群、 対照群（べヒクル投与群）、 正常群 (抗癌剤非投与群） の動物の全身の脱毛度合いを、 判定基準である脱毛スコアと して示した図である。  FIG. 1 is a diagram showing the degree of hair loss of the whole body of the test substance-administered group, control group (vehicle-administered group), and normal group (anti-cancer drug-non-administered group) in Example 1 as a hair loss score as a criterion. It is.
図 2は実施例 1における抗癌剤投与開始後 1 3日目の被験物質投与群の動物を 示した図である。  FIG. 2 is a diagram showing animals in a test substance administration group on day 13 after the start of anticancer drug administration in Example 1.
図 3は実施例 1における抗癌剤投与開始後 1 3日目の対照群の動物を示した図 である。  FIG. 3 is a diagram showing animals in a control group on day 13 after the start of anticancer drug administration in Example 1.
図 4は実施例 1における抗癌剤投与開始後 1 3日目の正常群の動物を示した図 である。  FIG. 4 is a diagram showing animals in a normal group on day 13 after the start of anticancer drug administration in Example 1.
図 5は実施例 2における被験物質投与群、 対照群（べヒクル投与群）、 正常群 (抗癌剤非投与群） の動物の全身の脱毛度合いを、 判定基準である脱毛スコアと して示した図である。  FIG. 5 is a diagram showing the degree of hair loss in the whole body of the test substance-administered group, the control group (vehicle-administered group), and the normal group (anti-cancer drug-non-administered group) in Example 2 as a hair loss score as a criterion. It is.
図 6は実施例 2における抗癌剤投与開始後 1 4日目の被験物質投与群の動物を 示した図である。  FIG. 6 is a diagram showing animals in a test substance administration group on day 14 after the start of anticancer drug administration in Example 2.
図 7は実施例 2における抗癌剤投与開始後 1 4日目の対照群の動物を示した図 乙 'ある。  FIG. 7 is a diagram showing animals in a control group on day 14 after the start of anticancer drug administration in Example 2.
図 8は実施例 2における抗癌剤投与開始後 1 4日目の正常群の動物を示した図 乙'ある。  FIG. 8 is a diagram showing animals in the normal group on day 14 after the start of anticancer drug administration in Example 2.
図 9は実施例 3における抜毛後 2 1日目の被検物質塗布群、 対照群（べヒクル 塗布群） の動物の脱毛度合いを、 抜毛面積に対する脱毛面積の百分率で示した図 乙 'ある。 Figure 9 shows the test substance-applied group and the control group (vehicle) on day 21 after hair removal in Example 3. Fig. 2 shows the degree of hair loss of the animals in the application group) as a percentage of the area of hair removal relative to the area of hair removal.
図 10は実施例 3における抜毛後 21日目の正常群 （抗癌剤非投与群） の動物 を示した図である。  FIG. 10 is a diagram showing the animals in the normal group (the group not administered with an anticancer drug) 21 days after hair removal in Example 3.
図 11は実施例 3における抜毛後 21日目の被検物質塗布群の動物を示した図 める ο  FIG. 11 shows the animals in the test substance application group 21 days after hair removal in Example 3.
図 12は実施例 3における抜毛後 21日目の対照群 （べヒクル塗布群） の動物 を示した図である。 発明を実施するための最良の形態  FIG. 12 is a diagram showing animals of a control group (vehicle-applied group) 21 days after hair removal in Example 3. BEST MODE FOR CARRYING OUT THE INVENTION
本発明の有効成分は、 一般式 X：銅（II) (式中、 Xはトリペプチドを示す） で表されるトリぺプチドー銅錯体であり、 トリベプチドの構成アミノ酸としては グリシン、 ァラニン、 /、'リ ン、 ロイシン、 イソロイシン、 セリ ン、 スレオニン、 システィ ン、 シスチン、 メチ才ニン、 ァスパラギン酸、 グルタ ミ ン酸、 リジン、 アルギニン、 フエ二ルァラニン、 チロシン、 ヒスチジン、 トリプトファン、 プロ リン、 ヒドロキシプロリンなどがあげられ、 これらのアミノ酸 3個を適宜組み合 わせて特表平 5— 505808号公報記載の方法で調製することができる。 なお、 アミノ酸は L体、 D体のいずれでもよい。  The active ingredient of the present invention is a triptide copper complex represented by the general formula X: copper (II) (wherein X represents a tripeptide), and the constituent amino acids of tribetide are glycine, alanine, /, 'Lin, leucine, isoleucine, serine, threonine, cystine, cystine, methine, aspartic acid, glutamic acid, lysine, arginine, phenylalanine, tyrosine, histidine, tryptophan, proline, hydroxyproline, etc. These amino acids can be prepared by a method described in JP-A-5-505808 by appropriately combining these three amino acids. The amino acid may be either L-form or D-form.
具体的には例えば、 L一ァラニルー L—ヒスチジル—L—リジン ：銅（11)、 グリシルー L—ヒスチジルー Lーリジン ：銅（11)、  Specifically, for example, L-alanyl-L-histidyl-L-lysine: copper (11), glycyl-L-histidyl L-lysine: copper (11),
L—ァラニル一 L一ヒスチジル一L—フエ二ルァラニン：銅（11)、 L-alanyl-L-histidyl-L-phenylalanine: copper (11),
Lーバリル一 L—ヒスチジル一L—リジン：銅（11)、 L-valyl-L-histidyl-L-lysine: copper (11),
L—プロリルー L—ヒスチジル一L一フヱニルァラニン ：銅（11)、 L-prolilu L-histidyl-L-phenylalanine: copper (11),
L—リジルー L—ヒスチジル—ダリシン：銅（II)などの錯体があげられる。 好ま しくは、 L—ァラニル一 L—ヒスチジル一L—リジン ：銅（11)、 グリシル一 L— ヒスチジル一L—リジン：銅（Π)があげられ、 特に好ましくは、 Lーァラニル一 L—ヒスチジルー L—リジン：銅（II)があげられる。 L-lysyl-L-histidyl-daricin: complexes such as copper (II). Preferably, L-alanyl-L-histidyl-L-lysine: copper (11), glycyl-L-histidyl-L-lysine: copper (Π), and particularly preferably, L-aralanyl-L-histidyl-L —Lysine: copper (II).
本発明における 「銅（Π)」 は二価の銅イオンを意味し、 トリペプチド—銅（II) 錯体におけるトリペプチド：銅（Π)のモル比率は適宜変えられるが、 特に 1 ： 1 〜2 ： 1が好ましい。 特に好ましいトリペプチド—銅（II)錯体としては、 例えば、 L—ァラニル一 L—ヒスチジルー L—リジン ：銅（Π) ( 1 ： 1 ) 、 ダリシル一 L —ヒスチジルー L一リジン：銅（II) ( 1 ： 1 )などがあげられ、 これらのトリべ プチド一銅錯体を単独であるいは二種以上の混合剤として使用できる。 In the present invention, “copper (Π)” means a divalent copper ion, and is a tripeptide-copper (II) Although the molar ratio of tripeptide: copper (Π) in the complex can be changed as appropriate, it is particularly preferably 1: 1 to 2: 1. Particularly preferred tripeptide-copper (II) complexes include, for example, L-alanyl-L-histidyl L-lysine: copper (Π) (1: 1), daricyl-L-histidyl L-lysine: copper (II) ( 1: 1), etc., and these triptotide-copper complexes can be used alone or as a mixture of two or more.
本発明の二次性脱毛予防 ·治療剤は、 医薬品、 医薬部外品または化粧品として 提供でき、 その剤型としては皮内注射剤のほか外用剤などにすることができる。 その製剤化には、 例えばクリーム、 ローション、 乳剤、 軟膏、 ゲルなどの基剤を 用いることができ、 必要に応じて防腐剤、 香料、 安定剤、 着色剤、 保湿剤、 増粘 剤など種々の添加剤を加えることもできる。  The agent for preventing or treating secondary hair loss of the present invention can be provided as a pharmaceutical, a quasi-drug, or a cosmetic, and its dosage form can be an intradermal injection or an external preparation. For the formulation, bases such as creams, lotions, emulsions, ointments and gels can be used.If necessary, various preservatives, fragrances, stabilizers, coloring agents, humectants, thickeners, etc. Additives can also be added.
本発明の二次性脱毛予防 ·治療剤の配合量は、 化学療法に用いられる薬剤の種 類や症状の度合い、 剤型などによって適宜変更できるが、 通常 0. 001〜10 重量％程度、 好ましくは 0. 01〜5重量％程度を製剤中に配合する。  The amount of the secondary hair loss preventing / treating agent of the present invention can be appropriately changed depending on the kind of the drug used in the chemotherapy, the degree of the symptom, the dosage form, etc., but is usually about 0.001 to 10% by weight, preferably. Is incorporated in the preparation in an amount of about 0.01 to 5% by weight.
本発明の二次性脱毛予防 ·治療剤の投与量は、 通常、 投与法、 剤形によって異 なるが、 成人で 1日当たり 0. l〜4m 1の範囲である。 この 1日投与量を 1日 1回あるいは数回に分けて投与する。 また 1日量は必要に応じて上記の量を超え て投与してもさしつかえない。 投与部位は頭皮が好ましい。  The dosage of the agent for preventing and treating secondary hair loss of the present invention usually varies depending on the administration method and dosage form, but is in the range of 0.1 to 4 ml per day for adults. This daily dose is administered once or several times a day. The daily dose may be larger than the above, if necessary. The site of administration is preferably on the scalp.
次に、 本発明の効果を示すための実施例をあげるが、 これらは本発明を何ら限 定するものではない。  Next, examples for showing the effects of the present invention will be described, but these do not limit the present invention at all.
<実施例 1 >ラッ ト化学療法モデル脱毛予防効果試験 <Example 1> Rat chemotherapy model hair loss prevention effect test
<試験方法 > <Test method>
Hu s s e i nらの方法 [S c i e n c e, Vo l. 249、 pp. 1564 — 1566 ( 1990) ] を一部改変して行った。 即ち、 生後 8日齢の SDラッ トの背部上下 2箇所に L一ァラニルー L—ヒスチジル—L—リジン：銅（II) ( 1 : 1 ) 0. 5%を含む生理食塩液の 0. 1m lを皮内投与する。 翌日より毎日 1 回、 抗癌剤シトシン一 1— 8-D—ァラビノフラノシド （以下 Ar a—Cと略す） を 25m gノ k gの投与量で腹腔内投与する。 脱毛予防効果の判定は、 全身およ び被験物質投与部位の脱毛状態について以下のようにスコア化して判定した。 な お、 対照群には生理食塩液のみを用いた。 The method of Hu ssein et al. [Science, Vol. 249, pp. 1564-1566 (1990)] was partially modified. That is, 0.1 ml of a physiological saline solution containing 0.5% of L-alanyl-L-histidyl-L-lysine: copper (II) (1: 1) is placed on the upper and lower portions of the back of an 8-day-old SD rat. Is administered intradermally. Once a day from the following day, the anticancer drug cytosine 1- 8-D-arabinofuranoside (hereinafter abbreviated as Ara-C) is intraperitoneally administered at a dose of 25 mg / kg. The hair loss preventing effect was determined by scoring the whole body and the hair loss state of the test substance administration site as follows. What In the control group, only physiological saline was used.
判定基準 スコア  Judgment criteria Score
正常 0  Normal 0
やや薄い 1  Slightly thin 1
明らかな脱毛（ 50%以下） 2  Obvious hair loss (less than 50%) 2
かなりの脱毛（ 50%以上） 3  Considerable hair loss (more than 50%) 3
完全脱毛 4  Complete hair removal 4
ぐ試験結果〉 Test results>
実施例 1の試験結果を図 1に示した。  The test results of Example 1 are shown in FIG.
抗癌剤を投与しない正常群（抗癌剤非投与群） では盛んな毛成長を示したのに 対し、 生理食塩液を投与した後、 抗癌剤を投与した対照群（べヒクル投与群） で は投与開始 6日目より脱毛症状が認められ、 9日目にはほぼ全身の体毛が脱毛し た。 本発明の 0. 5%被験物質投与群では、 投与部位に皮内投与による局所的な 瘢痕を残したが、 全身の体毛はほとんど脱毛せずに維持された。  The normal group without the anticancer drug (non-anticancer drug-administered group) showed vigorous hair growth, whereas the control group (vehicle-administered group) after administration of physiological saline and the anticancer drug after administration started on day 6 Alopecia was observed in the eyes, and on the ninth day almost all of the body hair was lost. In the group to which the 0.5% test substance of the present invention was administered, a local scar due to intradermal administration was left at the administration site, but the whole body hair was maintained with almost no hair loss.
抗癌剤投与開始後 13日目の被験物質投与群、 対照群、 正常群の動物の全身図 をそれぞれ図 2、 3、 4に示した。  The whole body of the test substance-administered group, control group, and normal group animals 13 days after the start of anticancer drug administration is shown in FIGS. 2, 3, and 4, respectively.
以上から明かなごとく、 Lーァラニル一 L—ヒスチジルー L—リジン：銅（Π) を投与することにより、 抗癌剤投与による二次性脱毛に対し有意に優れた予防効 果を示した。  As is clear from the above, administration of L-alanyl-l-histidyl-L-lysine: copper (II) showed a significantly superior preventive effect against secondary hair loss due to administration of an anticancer drug.
<実施例 2 >ラット化学療法モデル脱毛予防効果 <Example 2> Rat chemotherapy model hair loss prevention effect
<試験方法〉 <Test method>
生後 8日齢の SDラットの背部中央 1箇所に L—ァラニル— L一ヒスチジルー Lーリジン：銅（II) ( 1 : 1 ) 0. 25%を含む生理食塩液の 0. 05m 1を皮 内投与する。 翌日より毎日 1回、 Ar a— Cを 25mgZkgの投与量で腹腔内 投与する。 脱毛予防効果の判定は、 全身および被験物質投与部位の脱毛状態につ いて実施例 1と同様にしてスコア化して判定した。 なお、 対照群には生理食塩液 のみを用いた。  Intradermal administration of L-alanyl-L-histidine-L-lysine: Copper (II) (1: 1) 0.05 ml of a physiological saline solution containing 0.25% to one place at the center of the back of 8-day-old SD rats I do. From the next day, once a day, intraperitoneally administer Ar a-C at a dose of 25 mgZkg. The determination of the hair loss preventing effect was made by scoring the hair loss status of the whole body and the test substance administration site in the same manner as in Example 1. In the control group, only physiological saline was used.
ぐ試験結果 > 実施例 2の試験結果を図 5に示した。 Test results> The test results of Example 2 are shown in FIG.
正常群および対照群では実施例 1と同様な結果を示した。  The normal group and the control group showed the same results as in Example 1.
本発明の 0. 25%被験物質投与群では投与部位を除いたほぼ全身の体毛が対照 群と類似の脱毛パターンを示したが、 被験物質投与部位周辺では脱毛が予防され、 皮内投与による瘢痕も認められなかった。 In the 0.25% test substance administration group of the present invention, almost the whole body hair excluding the administration site showed a hair loss pattern similar to that of the control group, but hair loss was prevented around the test substance administration site, and scars due to intradermal administration were observed. Was also not recognized.
抗癌剤投与開始後 14日目の被験物質投与群、 対照群、 正常群の動物の全身図 をそれぞれ図 6、 7、 8に示した。  The whole body images of the test substance administration group, control group, and normal group animals on day 14 after the start of anticancer drug administration are shown in FIGS. 6, 7, and 8, respectively.
以上から明かなごとく、 L一ァラニルー L一ヒスチジルー L—リジン：銅（II) を投与することにより、 抗癌剤投与による二次性脱毛に対し有意に優れた予防効 果を示した。  As is apparent from the above, administration of L-alanyl-L-histidyl-L-lysine: copper (II) showed a significantly superior preventive effect against secondary hair loss due to administration of an anticancer drug.
<実施例 3〉マウス化学療法モデル脱毛予防効果（塗布試験）  <Example 3> Mouse chemotherapy model hair loss prevention effect (application test)
実施例 1および実施例 2において本発明物質の皮内投与による化学療法脱毛予防 効果が明らかにされた。 本発明物質を塗布することによつても脱毛予防効果を発 揮するか否か、 マウス化学療法脱毛モデルを用いて検討した。 In Example 1 and Example 2, the effect of preventing intradermal administration of the substance of the present invention for hair loss due to chemotherapy was clarified. Whether or not the application of the substance of the present invention exerts a hair loss preventing effect was examined using a mouse chemotherapy hair loss model.
く試験方法〉 Test method>
71日齢の C57BLマウス （雌） の肩背部のおよそ 5 cm2の体毛を、 ネンブ タール麻酔下に抜毛して成長期 （An a g e n ) を誘発する。 抜毛後、 8日目よ り 7日間、 毎日 2回 （朝、 夕）、 L—ァラニル一 L一ヒスチジル一L一リジン： 銅（II) ( 1 : 1 ) の 1%被検物質あるいはべヒクルの 0. 1m lを抜毛部に局所 塗布し、 10日目より、 被検物質あるいはべヒクル塗布（朝） の 2時間後に制癌 剤ドキソルビシン塩酸塩（4mgZk g ) を腹腔内に 1日 1回、 5日間投与する。 ドキソルビシン塩酸塩を投与終了した日より 7日後（抜毛後 21日目） に抜毛部 の脱毛面積を測定し、 抜毛面積の百分率として示した。 Approximately 5 cm 2 of the hair on the back of the shoulder of a 71-day-old C57BL mouse (female) is removed under Nembutal anesthesia to induce the anagen (Anagen). L-aranil-L-histidyl-L-lysine: 1% test substance or vehicle of copper (II) (1: 1) twice daily (morning and evening) for 7 days from the 8th day after hair removal 0.1 ml of the anti-cancer drug doxorubicin hydrochloride (4 mgZkg) intraperitoneally once a day 2 hours after application of the test substance or vehicle (morning) from day 10 Administer for 5 days. Seven days after the end of doxorubicin hydrochloride administration (21 days after hair removal), the area of hair removal in the hair removal part was measured and expressed as a percentage of the hair removal area.
被検物質塗布群および対照群（べヒクル塗布群） の抜毛後 21日目における脱 毛率を抜毛面積に対する脱毛面積の百分率として図 9に示した。  FIG. 9 shows the hair removal rate of the test substance-applied group and the control group (vehicle-applied group) on day 21 after hair removal as a percentage of the hair removal area to the hair removal area.
抜毛後 21日目の正常群（抗癌剤非投与群）、 被検物質塗布群、 対照群（べヒ クル塗布群） の動物の全身図をそれぞれ図 10、 11、 12に示した。  The whole body images of the normal group (anticancer drug-free group), the test substance-applied group, and the control group (vehicle-applied group) on day 21 after hair removal are shown in FIGS. 10, 11, and 12, respectively.
<試験結果〉 抜毛のみで、 被検物質塗布およびドキソルビシン塩酸塩の投与のいずれも行わ なかった正常群では、 抜毛後 21日目には抜毛部の体毛は完全に生え揃っていた。 これに対して、 ドキソルビシン塩酸塩を投与した群ではドキソルビシン塩酸塩 投与終了時までは正常群と同様、 体毛部全体に毛成長が認められたものの、 抜毛 後 21日目には、 対照群では抜毛部位での顕著な脱毛（脱毛率 69. 2%) が観 察された。 他方、 本発明物質を塗布した群ではそのような顕著な脱毛は観察され なかった （脱毛率 15. 0%)。 <Test results> In the normal group, where only the hair was removed and neither the test substance was applied nor the doxorubicin hydrochloride was administered, the hair at the removed portion was completely grown on the 21st day after the hair removal. On the other hand, in the group to which doxorubicin hydrochloride was administered, hair growth was observed in the whole body hair as in the normal group until the end of doxorubicin hydrochloride administration, but hair was removed in the control group on day 21 after hair removal. Significant hair loss at the site (hair loss rate 69.2%) was observed. On the other hand, such remarkable hair loss was not observed in the group to which the substance of the present invention was applied (hair removal rate: 15.0%).
以上より明らかなごとく、 L—ァラニルー L—ヒスチジルー Lーリジン：銅（I I )を塗布することによつても、 抗癌剤投与による二次性脱毛に対し有意に優れた 予防効果を示した。  As is clear from the above, application of L-alanyl-L-histidyl-L-lysine: copper (II) also exhibited a significantly superior preventive effect against secondary hair loss due to administration of an anticancer drug.
したがって、 本発明の二次性脱毛予防 ·治療剤が二次性脱毛に有効であること は上記実施例より明らかである。  Therefore, it is clear from the above Examples that the agent for preventing and treating secondary hair loss of the present invention is effective for secondary hair loss.
次に製剤処方例を示す。  Next, formulation examples are shown.
ぐ製剤例 > Preparation example>
L—ァラニル一 L一ヒスチジル一L—リジン ：銅（II) ( 1 ： 1 ) 500mgを 生理食塩液で全量 100m lになるように調製した。 産業上の利用可能性  500 mg of L-aralanyl-L-histidyl-L-lysine: copper (II) (1: 1) was prepared with physiological saline to a total volume of 100 ml. Industrial applicability
本発明の二次性脱毛予防 ·治療剤は、 卓越した効果を発揮する二次性脱毛の予 防および治療剤として有用である。  The preventive / therapeutic agent for secondary hair loss of the present invention is useful as a preventive and therapeutic agent for secondary hair loss that exhibits an excellent effect.

Claims

請 求 の 範 囲 The scope of the claims
1 . 一般式 X ：銅（I I) 1. General formula X: Copper (II)
(式中、 Xはトリぺプチドを示す） で表されるトリベプチドー銅錯体を含有する 二次性脱毛予防 ·治療剤。  (Wherein, X represents triptide) A secondary hair loss preventive / therapeutic agent comprising a tripeptide copper complex represented by the formula:
2. Xが Lーァラニル一 L—ヒスチジル一 Lーリジンであることを特徴とする請 求項 1に記載の二次性脱毛予防 ·治療剤。  2. The preventive and therapeutic agent for secondary hair loss according to claim 1, wherein X is L-alanyl-L-histidyl-L-lysine.
3 . 二次性脱毛を誘発する抗癌剤がシトシン一 1— /9— D—ァラビノフラノシド またはドキソルビシン塩酸塩であることを特徴とする請求項 1または 2に記載の 二次性脱毛予防 ·治療剤。  3. The secondary hair loss prevention according to claim 1 or 2, wherein the anticancer agent which induces secondary hair loss is cytosine 1- / 9-D-arabinofuranoside or doxorubicin hydrochloride. Therapeutic agent.
. 二次性脱毛予防 ·治療剤が塗布用製剤であることを特徴とする請求項 1ない し 3のいずれかに記載の二次性脱毛予防 ·治療剤。  4. The agent for preventing or treating secondary hair loss according to any one of claims 1 to 3, wherein the agent for preventing or treating secondary hair loss is a preparation for application.
5. 請求項 1ないし 4のいずれかに記載の二次性脱毛予防 ·治療剤を用いた二次 性脱毛の予防および治療方法。  5. A method for preventing and treating secondary hair loss using the preventive and therapeutic agent for secondary hair loss according to any one of claims 1 to 4.
6. 投与部位が頭部であることを特徴とする請求項 5に記載の二次性脱毛の予防 および治療方法。  6. The method for preventing and treating secondary hair loss according to claim 5, wherein the administration site is a head.
7 . 投与方法が塗布であることを特徴とする請求項 5または 6に記載の二次性脱 毛の予防および治療方法。  7. The method for preventing and treating secondary hair loss according to claim 5 or 6, wherein the administration method is application.
PCT/JP1995/000350 1994-03-03 1995-03-03 Preventive and remedy for secondary depilation WO1995023580A1 (en)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
JP2005504063A (en) * 2001-09-03 2005-02-10 リシャール・ヴェルミー Compositions and methods related to prevention of chemotherapy-induced hair loss
JP2006504448A (en) * 2002-07-02 2006-02-09 プロサイト コーポレイション Composition containing peptide copper complex and soft tissue filler
JP2007516209A (en) * 2003-07-18 2007-06-21 アンスティテュ・ヨーロペアン・ドゥ・ビョロジ・セリュレール Use of peptide conjugates for the manufacture of compositions for the prevention and therapeutic treatment of alopecia
WO2021247531A1 (en) * 2020-06-01 2021-12-09 Balchem Corporation Metal di-amino acid chelates or metal tri-amino acid chelates

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JPH05501567A (en) * 1989-11-13 1993-03-25 プロサイト　コーポレーション Metal-peptide compositions and methods for stimulating hair growth
JPH06305941A (en) * 1993-04-15 1994-11-01 Procyte Corp Medicine and make-up goods to promote growth of hair

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Publication number Priority date Publication date Assignee Title
JPH05501567A (en) * 1989-11-13 1993-03-25 プロサイト　コーポレーション Metal-peptide compositions and methods for stimulating hair growth
JPH06305941A (en) * 1993-04-15 1994-11-01 Procyte Corp Medicine and make-up goods to promote growth of hair

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005504063A (en) * 2001-09-03 2005-02-10 リシャール・ヴェルミー Compositions and methods related to prevention of chemotherapy-induced hair loss
JP2006504448A (en) * 2002-07-02 2006-02-09 プロサイト コーポレイション Composition containing peptide copper complex and soft tissue filler
JP2007516209A (en) * 2003-07-18 2007-06-21 アンスティテュ・ヨーロペアン・ドゥ・ビョロジ・セリュレール Use of peptide conjugates for the manufacture of compositions for the prevention and therapeutic treatment of alopecia
JP2013010769A (en) * 2003-07-18 2013-01-17 Inst Europeen De Biologie Cellulair Use of peptide conjugate for preparing composition for alopecia preventive and curative treatment
JP2015134777A (en) * 2003-07-18 2015-07-27 アンスティテュ・ヨーロペアン・ドゥ・ビョロジ・セリュレールＩｎｓｔｉｔｕｔ Ｅｕｒｏｐｅｅｎ Ｄｅ Ｂｉｏｌｏｇｉｅ Ｃｅｌｌｕｌａｉｒｅ Use of peptidic conjugates for preparing compositions for alopecia preventive and curative treatment
WO2021247531A1 (en) * 2020-06-01 2021-12-09 Balchem Corporation Metal di-amino acid chelates or metal tri-amino acid chelates

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